Cosmic string

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cosmic_string

Cosmic strings are hypothetical 1-dimensional topological defects which may have formed during a symmetry-breaking phase transition in the early universe when the topology of the vacuum manifold associated to this symmetry breaking was not simply connected.

In less formal terms, they are hypothetical long, thin defects in the fabric of space. They might have formed in the early universe during a process where certain symmetries were broken. Their existence was first contemplated by the theoretical physicist Tom Kibble in the 1970s.

The formation of cosmic strings is somewhat analogous to the imperfections that form between crystal grains in solidifying liquids, or the cracks that form when water freezes into ice. The phase transitions leading to the production of cosmic strings are likely to have occurred during the earliest moments of the universe's evolution, just after cosmological inflation, and are a fairly generic prediction in both quantum field theory and string theory models of the early universe.

Theories containing cosmic strings

The prototypical example of a field theory with cosmic strings is the Abelian Higgs model. The quantum field theory and string theory cosmic strings are expected to have many properties in common, but more research is needed to determine the precise distinguishing features. The F-strings for instance are fully quantum-mechanical and do not have a classical definition, whereas the field theory cosmic strings are almost exclusively treated classically.

In superstring theory, the role of cosmic strings can be played by the fundamental strings (or F-strings) themselves that define the theory perturbatively, by D-strings which are related to the F-strings by weak-strong or so called S-duality, or higher-dimensional D-, NS- or M-branes that are partially wrapped on compact cycles associated to extra spacetime dimensions so that only one non-compact dimension remains.

Dimensions

Cosmic strings, if they exist, would be extremely thin topological defects with diameters of the same order of magnitude as that of a proton, i.e. ~1 fm, or smaller. Given that this scale is much smaller than any cosmological scale, these strings are often studied in the zero-width, or Nambu–Goto approximation. Under this assumption, strings behave as one-dimensional objects and obey the Nambu–Goto action, which is classically equivalent to the Polyakov action that defines the bosonic sector of superstring theory.

In field theory, the string width is set by the scale of the symmetry-breaking phase transition. In string theory, the string width is set (in the simplest cases) by the fundamental string scale, warp factors (associated to the spacetime curvature of an internal six-dimensional spacetime manifold) and/or the size of internal compact dimensions. (In string theory, the universe is either 10- or 11-dimensional, depending on the strength of interactions and the curvature of spacetime.)

Gravitation

A string is a geometrical deviation from Euclidean geometry in spacetime characterized by an angular deficit: a circle around the outside of a string would comprise a total angle less than 360°. From the general theory of relativity such a geometrical defect must be in tension, and would be manifested by mass. Even though cosmic strings are thought to be extremely thin, they would have immense density, and so would represent significant gravitational wave sources. A cosmic string about a kilometer in length may be more massive than the Earth.

However general relativity predicts that the gravitational potential of a straight string vanishes: there is no gravitational force on static surrounding matter. The only gravitational effect of a straight cosmic string is a relative deflection of matter (or light) passing the string on opposite sides (a purely topological effect). A closed cosmic string gravitates in a more conventional way.

During the expansion of the universe, cosmic strings would form a network of loops, and in the past it was thought that their gravity could have been responsible for the original clumping of matter into galactic superclusters. It is now calculated that their contribution to the structure formation in the universe is less than 10%.

Negative mass cosmic string

The standard model of a cosmic string is a geometrical structure with an angle deficit, which thus is in tension and hence has positive mass. In 1995, Visser et al. proposed that cosmic strings could theoretically also exist with angle excesses, and thus negative tension and hence negative mass. The stability of such exotic matter strings is problematic; however, they suggested that if a negative mass string were to be wrapped around a wormhole in the early universe, such a wormhole could be stabilized sufficiently to exist in the present day.

Super-critical cosmic string

The exterior geometry of a (straight) cosmic string can be visualized in an embedding diagram as follows: Focusing on the two-dimensional surface perpendicular to the string, its geometry is that of a cone which is obtained by cutting out a wedge of angle δ and gluing together the edges. The angular deficit δ is linearly related to the string tension (= mass per unit length), i.e. the larger the tension, the steeper the cone. Therefore, δ reaches 2π for a certain critical value of the tension, and the cone degenerates to a cylinder. (In visualizing this setup one has to think of a string with a finite thickness.) For even larger, "super-critical" values, δ exceeds 2π and the (two-dimensional) exterior geometry closes up (it becomes compact), ending in a conical singularity.

However, this static geometry is unstable in the super-critical case (unlike for sub-critical tensions): Small perturbations lead to a dynamical spacetime which expands in axial direction at a constant rate. The 2D exterior is still compact, but the conical singularity can be avoided, and the embedding picture is that of a growing cigar. For even larger tensions (exceeding the critical value by approximately a factor of 1.6), the string cannot be stabilized in radial direction anymore.

Realistic cosmic strings are expected to have tensions around 6 orders of magnitude below the critical value, and are thus always sub-critical. However, the inflating cosmic string solutions might be relevant in the context of brane cosmology, where the string is promoted to a 3-brane (corresponding to our universe) in a six-dimensional bulk.

Observational evidence

It was once thought that the gravitational influence of cosmic strings might contribute to the large-scale clumping of matter in the universe, but all that is known today through galaxy surveys and precision measurements of the cosmic microwave background (CMB) fits an evolution out of random, gaussian fluctuations. These precise observations therefore tend to rule out a significant role for cosmic strings and currently it is known that the contribution of cosmic strings to the CMB cannot be more than 10%.

The violent oscillations of cosmic strings generically lead to the formation of cusps and kinks. These in turn cause parts of the string to pinch off into isolated loops. These loops have a finite lifespan and decay (primarily) via gravitational radiation. This radiation which leads to the strongest signal from cosmic strings may in turn be detectable in gravitational wave observatories. An important open question is to what extent do the pinched off loops backreact or change the initial state of the emitting cosmic string—such backreaction effects are almost always neglected in computations and are known to be important, even for order of magnitude estimates.

Gravitational lensing of a galaxy by a straight section of a cosmic string would produce two identical, undistorted images of the galaxy. In 2003 a group led by Mikhail Sazhin reported the accidental discovery of two seemingly identical galaxies very close together in the sky, leading to speculation that a cosmic string had been found. However, observations by the Hubble Space Telescope in January 2005 showed them to be a pair of similar galaxies, not two images of the same galaxy. A cosmic string would produce a similar duplicate image of fluctuations in the cosmic microwave background, which it was thought might have been detectable by the Planck Surveyor mission. However, a 2013 analysis of data from the Planck mission failed to find any evidence of cosmic strings.

A piece of evidence supporting cosmic string theory is a phenomenon noticed in observations of the "double quasar" called Q0957+561A,B. Originally discovered by Dennis Walsh, Bob Carswell, and Ray Weymann in 1979, the double image of this quasar is caused by a galaxy positioned between it and the Earth. The gravitational lens effect of this intermediate galaxy bends the quasar's light so that it follows two paths of different lengths to Earth. The result is that we see two images of the same quasar, one arriving a short time after the other (about 417.1 days later). However, a team of astronomers at the Harvard-Smithsonian Center for Astrophysics led by Rudolph Schild studied the quasar and found that during the period between September 1994 and July 1995 the two images appeared to have no time delay; changes in the brightness of the two images occurred simultaneously on four separate occasions. Schild and his team believe that the only explanation for this observation is that a cosmic string passed between the Earth and the quasar during that time period traveling at very high speed and oscillating with a period of about 100 days.

Until 2023 the most sensitive bounds on cosmic string parameters came from the non-detection of gravitational waves by pulsar timing array data. The first detection of gravitational waves with pulsar timing array was confirmed in 2023. The earthbound Laser Interferometer Gravitational-Wave Observatory (LIGO) and especially the space-based gravitational wave detector Laser Interferometer Space Antenna (LISA) will search for gravitational waves and are likely to be sensitive enough to detect signals from cosmic strings, provided the relevant cosmic string tensions are not too small.

String theory and cosmic strings

During the early days of string theory both string theorists and cosmic string theorists believed that there was no direct connection between superstrings and cosmic strings (the names were chosen independently by analogy with ordinary string). The possibility of cosmic strings being produced in the early universe was first envisioned by quantum field theorist Tom Kibble in 1976, and this sprouted the first flurry of interest in the field.

In 1985, during the first superstring revolution, Edward Witten contemplated on the possibility of fundamental superstrings having been produced in the early universe and stretched to macroscopic scales, in which case (following the nomenclature of Tom Kibble) they would then be referred to as cosmic superstrings. He concluded that had they been produced they would have either disintegrated into smaller strings before ever reaching macroscopic scales (in the case of Type I superstring theory), they would always appear as boundaries of domain walls whose tension would force the strings to collapse rather than grow to cosmic scales (in the context of heterotic superstring theory), or having a characteristic energy scale close to the Planck energy they would be produced before cosmological inflation and hence be diluted away with the expansion of the universe and not be observable.

Much has changed since these early days, primarily due to the second superstring revolution. It is now known that string theory contains, in addition to the fundamental strings which define the theory perturbatively, other one-dimensional objects, such as D-strings, and higher-dimensional objects such as D-branes, NS-branes and M-branes partially wrapped on compact internal spacetime dimensions, while being spatially extended in one non-compact dimension. The possibility of large compact dimensions and large warp factors allows strings with tension much lower than the Planck scale.

Furthermore, various dualities that have been discovered point to the conclusion that actually all these apparently different types of string are just the same object as it appears in different regions of parameter space. These new developments have largely revived interest in cosmic strings, starting in the early 2000s.

In 2002, Henry Tye and collaborators predicted the production of cosmic superstrings during the last stages of brane inflation, a string theory construction of the early universe that gives leads to an expanding universe and cosmological inflation. It was subsequently realized by string theorist Joseph Polchinski that the expanding Universe could have stretched a "fundamental" string (the sort which superstring theory considers) until it was of intergalactic size. Such a stretched string would exhibit many of the properties of the old "cosmic" string variety, making the older calculations useful again. As theorist Tom Kibble remarks, "string theory cosmologists have discovered cosmic strings lurking everywhere in the undergrowth". Older proposals for detecting cosmic strings could now be used to investigate superstring theory.

Superstrings, D-strings or the other stringy objects mentioned above stretched to intergalactic scales would radiate gravitational waves, which could be detected using experiments like LIGO and especially the space-based gravitational wave experiment LISA. They might also cause slight irregularities in the cosmic microwave background, too subtle to have been detected yet but possibly within the realm of future observability.

Note that most of these proposals depend, however, on the appropriate cosmological fundamentals (strings, branes, etc.), and no convincing experimental verification of these has been confirmed to date. Cosmic strings nevertheless provide a window into string theory. If cosmic strings are observed, which is a real possibility for a wide range of cosmological string models, this would provide the first experimental evidence of a string theory model underlying the structure of spacetime.

Cosmic string network

There are many attempts to detect the footprint of a cosmic strings network.

Potential applications

In 1986, John G. Cramer proposed that spacecraft equipped with magnet coils could travel along cosmic strings, analogous to how a maglev train travels along a rail line.

Punctuated equilibrium

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Punctuated_equilibrium

The punctuated equilibrium model (top) consists of morphological stability followed by rare bursts of evolutionary change via rapid cladogenesis – vertical equilibrium states separated by horizontal "jump" phases. In contrast, phyletic gradualism (below), is a more gradual, continuous model of evolution – with accumulation of small incremental changes represented by slanted bars that split at branch-points, where two separate modes of life are feasible but of which, each prospers best with divergent specializations.

In evolutionary biology, punctuated equilibrium (also called punctuated equilibria) is a theory that proposes that once a species appears in the fossil record, the population will become stable, showing little evolutionary change for most of its geological history. This state of little or no morphological change is called stasis. When significant evolutionary change occurs, the theory proposes that it is generally restricted to rare and geologically rapid events of branching speciation called cladogenesis. Cladogenesis is the process by which a species splits into two distinct species, rather than one species gradually transforming into another.

Punctuated equilibrium is commonly contrasted with phyletic gradualism, the idea that evolution generally occurs uniformly by the steady and gradual transformation of whole lineages (anagenesis).

In 1972, paleontologists Niles Eldredge and Stephen Jay Gould published a landmark paper developing their theory and called it punctuated equilibria. Their paper built upon Ernst Mayr's model of geographic speciation, I. M. Lerner's theories of developmental and genetic homeostasis, and their own empirical research. Eldredge and Gould proposed that the degree of gradualism commonly attributed to Charles Darwin is virtually nonexistent in the fossil record, and that stasis dominates the history of most fossil species.

History

Punctuated equilibrium originated as a logical consequence of Ernst Mayr's concept of genetic revolutions by allopatric and especially peripatric speciation as applied to the fossil record. Although the sudden appearance of species and its relationship to speciation was proposed and identified by Mayr in 1954, historians of science generally recognize the 1972 Eldredge and Gould paper as the basis of the new paleobiological research program. Punctuated equilibrium differs from Mayr's ideas mainly in that Eldredge and Gould placed considerably greater emphasis on stasis, whereas Mayr was concerned with explaining the morphological discontinuity (or "sudden jumps") found in the fossil record. Mayr later complimented Eldredge and Gould's paper, stating that evolutionary stasis had been "unexpected by most evolutionary biologists" and that punctuated equilibrium "had a major impact on paleontology and evolutionary biology."

A year before his and Gould's 1972 paper, Niles Eldredge published a paper in the journal Evolution which suggested that gradual evolution was seldom seen in the fossil record and argued that Ernst Mayr's standard mechanism of allopatric speciation might suggest a possible resolution.

The Eldredge and Gould paper was presented at the Annual Meeting of the Geological Society of America in 1971. The symposium focused its attention on how modern microevolutionary studies could revitalize various aspects of paleontology and macroevolution. Tom Schopf, who organized that year's meeting, assigned Gould the topic of speciation. Gould recalls that "Eldredge's 1971 publication [on Paleozoic trilobites] had presented the only new and interesting ideas on the paleontological implications of the subject—so I asked Schopf if we could present the paper jointly." According to Gould "the ideas came mostly from Niles, with yours truly acting as a sounding board and eventual scribe. I coined the term punctuated equilibrium and wrote most of our 1972 paper, but Niles is the proper first author in our pairing of Eldredge and Gould." In his book Time Frames Eldredge recalls that after much discussion the pair "each wrote roughly half. Some of the parts that would seem obviously the work of one of us were actually first penned by the other—I remember for example, writing the section on Gould's snails. Other parts are harder to reconstruct. Gould edited the entire manuscript for better consistency. We sent it in, and Schopf reacted strongly against it—thus signaling the tenor of the reaction it has engendered, though for shifting reasons, down to the present day."

John Wilkins and Gareth Nelson have argued that French architect Pierre Trémaux proposed an "anticipation of the theory of punctuated equilibrium of Gould and Eldredge."

Evidence from the fossil record

Main article: Rate of evolution

The fossil record includes well documented examples of both phyletic gradualism and punctuational evolution. As such, much debate persists over the prominence of stasis in the fossil record.Before punctuated equilibrium, most evolution biologists considered stasis to be rare or unimportant.The paleontologist George Gaylord Simpson, for example, believed that phyletic gradual evolution (called horotely in his terminology) comprised 90% of evolution. More modern studies, including a meta-analysis examining 58 published studies on speciation patterns in the fossil record showed that 71% of species exhibited stasis, and 63% were associated with punctuated patterns of evolutionary change. According to Michael Benton, "it seems clear then that stasis is common, and that had not been predicted from modern genetic studies." A paramount example of evolutionary stasis is the fern Osmunda claytoniana. Based on paleontological evidence it has remained unchanged, even at the level of fossilized nuclei and chromosomes, for at least 180 million years.

Theoretical mechanisms

Punctuational change

When Eldredge and Gould published their 1972 paper, allopatric speciation was considered the "standard" model of speciation. This model was popularized by Ernst Mayr in his 1954 paper "Change of genetic environment and evolution," and his classic volume Animal Species and Evolution (1963).

Allopatric speciation suggests that species with large central populations are stabilized by their large volume and the process of gene flow. New and even beneficial mutations are diluted by the population's large size and are unable to reach fixation, due to such factors as constantly changing environments. If this is the case, then the transformation of whole lineages should be rare, as the fossil record indicates. Smaller populations on the other hand, which are isolated from the parental stock, are decoupled from the homogenizing effects of gene flow. In addition, pressure from natural selection is especially intense, as peripheral isolated populations exist at the outer edges of ecological tolerance. If most evolution happens in these rare instances of allopatric speciation then evidence of gradual evolution in the fossil record should be rare. This hypothesis was alluded to by Mayr in the closing paragraph of his 1954 paper:

Rapidly evolving peripherally isolated populations may be the place of origin of many evolutionary novelties. Their isolation and comparatively small size may explain phenomena of rapid evolution and lack of documentation in the fossil record, hitherto puzzling to the palaeontologist.

Although punctuated equilibrium generally applies to sexually reproducing organisms, some biologists have applied the model to non-sexual species like viruses, which cannot be stabilized by conventional gene flow. As time went on biologists like Gould moved away from wedding punctuated equilibrium to allopatric speciation, particularly as evidence accumulated in support of other modes of speciation. Gould, for example, was particularly attracted to Douglas Futuyma's work on the importance of reproductive isolating mechanisms.

Stasis

Many hypotheses have been proposed to explain the putative causes of stasis. Gould was initially attracted to I. Michael Lerner's theories of developmental and genetic homeostasis. However this hypothesis was rejected over time, as evidence accumulated against it. Other plausible mechanisms which have been suggested include: habitat tracking, stabilizing selection, the Stenseth-Maynard Smith stability hypothesis, constraints imposed by the nature of subdivided populations, normalizing clade selection, and koinophilia.

Evidence for stasis has also been corroborated from the genetics of sibling species, species which are morphologically indistinguishable, but whose proteins have diverged sufficiently to suggest they have been separated for millions of years. Fossil evidence of reproductively isolated extant species of sympatric Olive Shells (Amalda sp.) also confirm morphological stasis in multiple lineages over three million years.

According to Gould, "stasis may emerge as the theory's most important contribution to evolutionary science." Philosopher Kim Sterelny in clarifying the meaning of stasis adds, "In claiming that species typically undergo no further evolutionary change once speciation is complete, they are not claiming that there is no change at all between one generation and the next. Lineages do change. But the change between generations does not accumulate. Instead, over time, the species wobbles about its phenotypic mean. Jonathan Weiner's The Beak of the Finch describes this very process."

Hierarchical evolution

Punctuated equilibrium has also been cited as contributing to the hypothesis that species are Darwinian individuals, and not just classes, thereby providing a stronger framework for a hierarchical theory of evolution.

Common misconceptions

Much confusion has arisen over what proponents of punctuated equilibrium actually argued, what mechanisms they advocated, how fast the punctuations were, what taxonomic scale their theory applied to, how revolutionary their claims were intended to be, and how punctuated equilibrium related to other ideas like saltationism, quantum evolution, and mass extinction.

Saltationism

Alternative explanations for the punctuated pattern of evolution observed in the fossil record. Both macromutation and seemingly "rapid" episodes of gradual evolution could give the appearance of instantaneous change, since 10,000 years seldom registers in the geological record.

The punctuational nature of punctuated equilibrium has engendered perhaps the most confusion over Eldredge and Gould's theory. Gould's sympathetic treatment of Richard Goldschmidt, the controversial geneticist who advocated the idea of "hopeful monsters," led some biologists to conclude that Gould's punctuations were occurring in single-generation jumps. This interpretation has frequently been used by creationists to characterize the weakness of the paleontological record, and to portray contemporary evolutionary biology as advancing neo-saltationism.

In an often quoted remark, Gould stated,

"Since we proposed punctuated equilibria to explain trends, it is infuriating to be quoted again and again by creationists – whether through design or stupidity, I do not know – as admitting that the fossil record includes no transitional forms. Transitional forms are generally lacking at the species level, but they are abundant between larger groups."

Although there exist some debate over how long the punctuations last, supporters of punctuated equilibrium generally place the figure between 50,000 and 100,000 years.

Quantum evolution

Quantum evolution was a controversial hypothesis advanced by Columbia University paleontologist George Gaylord Simpson, regarded by Gould as "the greatest and most biologically astute paleontologist of the twentieth century." Simpson's conjecture was that according to the geological record, on very rare occasions evolution would proceed very rapidly to form entirely new families, orders, and classes of organisms. This hypothesis differs from punctuated equilibrium in several respects. First, punctuated equilibrium was more modest in scope, in that it was addressing evolution specifically at the species level. Simpson's idea was principally concerned with evolution at higher taxonomic groups. Second, Eldredge and Gould relied upon a different mechanism. Where Simpson relied upon a synergistic interaction between genetic drift and a shift in the adaptive fitness landscape, Eldredge and Gould relied upon ordinary speciation, particularly Ernst Mayr's concept of allopatric speciation. Lastly, and perhaps most significantly, quantum evolution took no position on the issue of stasis. Although Simpson acknowledged the existence of stasis in what he called the bradytelic mode, he considered it (along with rapid evolution) to be unimportant in the larger scope of evolution. In his Major Features of Evolution Simpson stated, "Evolutionary change is so nearly the universal rule that a state of motion is, figuratively, normal in evolving populations. The state of rest, as in bradytely, is the exception and it seems that some restraint or force must be required to maintain it." Despite such differences between the two models, earlier critiques—from such eminent commentators as Sewall Wright as well as Simpson himself—have argued that punctuated equilibrium is little more than quantum evolution relabeled.

Multiple meanings of gradualism

Punctuated equilibrium is often portrayed to oppose the concept of gradualism, when it is actually a form of gradualism. This is because even though evolutionary change appears instantaneous between geological sedimentary layers, change is still occurring incrementally, with no great change from one generation to the next. To this end, Gould later commented that "Most of our paleontological colleagues missed this insight because they had not studied evolutionary theory and either did not know about allopatric speciation or had not considered its translation to geological time. Our evolutionary colleagues also failed to grasp the implication(s), primarily because they did not think at geological scales".

Richard Dawkins dedicates a chapter in The Blind Watchmaker to correcting, in his view, the wide confusion regarding rates of change. His first point is to argue that phyletic gradualism—understood in the sense that evolution proceeds at a single uniform speed, called "constant speedism" by Dawkins—is a "caricature of Darwinism" and "does not really exist". His second argument, which follows from the first, is that once the caricature of "constant speedism" is dismissed, we are left with one logical alternative, which Dawkins terms "variable speedism". Variable speedism may also be distinguished one of two ways: "discrete variable speedism" and "continuously variable speedism". Eldredge and Gould, proposing that evolution jumps between stability and relative rapidity, are described as "discrete variable speedists", and "in this respect they are genuinely radical." They assert that evolution generally proceeds in bursts, or not at all. "Continuously variable speedists", on the other hand, advance that "evolutionary rates fluctuate continuously from very fast to very slow and stop, with all intermediates. They see no particular reason to emphasize certain speeds more than others. In particular, stasis, to them, is just an extreme case of ultra-slow evolution. To a punctuationist, there is something very special about stasis."

Criticism

See also: Species problem, Species complex, and Push of the past

Richard Dawkins regards the apparent gaps represented in the fossil record as documenting migratory events rather than evolutionary events. According to Dawkins, evolution certainly occurred but "probably gradually" elsewhere. However, the punctuational equilibrium model may still be inferred from both the observation of stasis and examples of rapid and episodic speciation events documented in the fossil record.

Dawkins also emphasizes that punctuated equilibrium has been "oversold by some journalists", but partly due to Eldredge and Gould's "later writings". Dawkins contends that the hypothesis "does not deserve a particularly large measure of publicity". It is a "minor gloss," an "interesting but minor wrinkle on the surface of neo-Darwinian theory," and "lies firmly within the neo-Darwinian synthesis".

In his book Darwin's Dangerous Idea, philosopher Daniel Dennett is especially critical of Gould's presentation of punctuated equilibrium. Dennett argues that Gould alternated between revolutionary and conservative claims, and that each time Gould made a revolutionary statement—or appeared to do so—he was criticized, and thus retreated to a traditional neo-Darwinian position. Gould responded to Dennett's claims in The New York Review of Books, and in his technical volume The Structure of Evolutionary Theory.

English professor Heidi Scott argues that Gould's talent for writing vivid prose, his use of metaphor, and his success in building a popular audience of nonspecialist readers altered the "climate of specialized scientific discourse" favorably in his promotion of punctuated equilibrium. While Gould is celebrated for the color and energy of his prose, as well as his interdisciplinary knowledge, critics such as Scott, Richard Dawkins, and Daniel Dennett have concerns that the theory has gained undeserved credence among non-scientists because of Gould's rhetorical skills. Philosopher John Lyne and biologist Henry Howe believed punctuated equilibrium's success has much more to do with the nature of the geological record than the nature of Gould's rhetoric. They state, a "re-analysis of existing fossil data has shown, to the increasing satisfaction of the paleontological community, that Eldredge and Gould were correct in identifying periods of evolutionary stasis which are interrupted by much shorter periods of evolutionary change."

Evolutionary biologist Robert Trivers accused Gould of being "something of an intellectual fraud" for using claims that were "well known from the time of Darwin" (that evolution displayed "periods of long stasis interspersed with periods of rapid change") to support distinct but more "grandiose" claims regarding species selection, despite the "rate of species turnover [having] nothing to do with the traits within species—only with the relative frequency of species showing these traits".

Some critics jokingly referred to the theory of punctuated equilibrium as "evolution by jerks", which reportedly prompted punctuationists to describe phyletic gradualism as "evolution by creeps."

Darwin's theory

The sudden appearance of most species in the geologic record and the lack of evidence of substantial gradual change in most species—from their initial appearance until their extinction—has long been noted, including by Charles Darwin, who appealed to the imperfection of the record as the favored explanation. When presenting his ideas against the prevailing influences of catastrophism and progressive creationism, which envisaged species being supernaturally created at intervals, Darwin needed to forcefully stress the gradual nature of evolution in accordance with the gradualism promoted by his friend Charles Lyell. He privately expressed concern, noting in the margin of his 1844 Essay, "Better begin with this: If species really, after catastrophes, created in showers world over, my theory false."

It is often incorrectly assumed that he insisted that the rate of change must be constant, or nearly so, but even the first edition of On the Origin of Species states that "Species of different genera and classes have not changed at the same rate, or in the same degree. In the oldest tertiary beds a few living shells may still be found in the midst of a multitude of extinct forms... The Silurian Lingula differs but little from the living species of this genus". Lingula is among the few brachiopods surviving today but also known from fossils over 500 million years old. In the fourth edition (1866) of On the Origin of Species Darwin wrote that "the periods during which species have undergone modification, though long as measured in years, have probably been short in comparison with the periods during which they retain the same form." Thus punctuationism in general is consistent with Darwin's conception of evolution.

According to early versions of punctuated equilibrium, "peripheral isolates" are considered to be of critical importance for speciation. However, Darwin wrote, "I can by no means agree ... that immigration and isolation are necessary elements. ... Although isolation is of great importance in the production of new species, on the whole I am inclined to believe that largeness of area is still more important, especially for the production of species which shall prove capable of enduring for a long period, and of spreading widely."

The importance of isolation in forming species had played a significant part in Darwin's early thinking, as shown in his Essay of 1844. But by the time he wrote the Origin he had downplayed its importance. He explained the reasons for his revised view as follows:

Throughout a great and open area, not only will there be a greater chance of favourable variations, arising from the large number of individuals of the same species there supported, but the conditions of life are much more complex from the large number of already existing species; and if some of these species become modified and improved, others will have to be improved in a corresponding degree, or they will be exterminated. Each new form, also, as soon as it has been improved, will be able to spread over the open and continuous area, and will thus come into competition with many other forms ... the new forms produced on large areas, which have already been victorious over many competitors, will be those that will spread most widely, and will give rise to the greatest number of new varieties and species. They will thus play a more important role in the changing history of the organic world.

Thus punctuated equilibrium is incongruous with some of Darwin's ideas regarding the specific mechanisms of evolution, but generally accords with Darwin's theory of evolution by natural selection.

Supplemental modes of rapid evolution

See also: Rapid modes of evolution

Recent work in developmental biology has identified dynamical and physical mechanisms of tissue morphogenesis that may underlie abrupt morphological transitions during evolution. Consequently, consideration of mechanisms of phylogenetic change that have been found in reality to be non-gradual is increasingly common in the field of evolutionary developmental biology, particularly in studies of the origin of morphological novelty. A description of such mechanisms can be found in the multi-authored volume Origination of Organismal Form (MIT Press; 2003).

Language change

For broader coverage of this topic, see Language change.

In linguistics, R. M. W. Dixon has proposed a punctuated equilibrium model for language histories, with reference particularly to the prehistory of the indigenous languages of Australia and his objections to the proposed Pama–Nyungan language family there. Although his model has raised considerable interest, it does not command majority support within linguistics.

Separately, recent work using computational phylogenetic methods claims to show that punctuational bursts play an important factor when languages split from one another, accounting for anywhere from 10 to 33% of the total divergence in vocabulary, and around 24% of divergence among cognates in the Indo-European language family.

Mythology

Punctuational evolution has been argued to explain changes in folktales and mythology over time.

Neurodegenerative disease

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Neurodegenerative_disease

 

Neurodegenerative disease
Normal brain on left contrasted with structural changes shown in brain on right of person with Alzheimer's disease, the most common neurodegenerative disease
Specialty	Neurology, Psychiatry

A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies (like proteinopathy) and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

Within neurodegenerative diseases, it is estimated that 55 million people worldwide had dementia in 2019, and that by 2050 this figure will increase to 139 million people.

Specific disorders

The consequences of neurodegeneration can vary widely depending on the specific region affected, ranging from issues related to movement to the development of dementia.

Alzheimer's disease

Comparison of brain tissue between healthy individual and Alzheimer's disease patient, demonstrating extent of neuronal death

Main article: Alzheimer's disease

Alzheimer's disease (AD) is a chronic neurodegenerative disease that results in the loss of neurons and synapses in the cerebral cortex and certain subcortical structures, resulting in gross atrophy of the temporal lobe, parietal lobe, and parts of the frontal cortex and cingulate gyrus. It is the most common neurodegenerative disease. Even with billions of dollars being used to find a treatment for Alzheimer's disease, no effective treatments have been found. Within clinical trials stable and effective AD therapeutic strategies have a 99.5% failure rate. Reasons for this failure rate include inappropriate drug doses, invalid target and participant selection, and inadequate knowledge of pathophysiology of AD. Currently, diagnoses of Alzheimer's is subpar, and better methods need to be utilized for various aspects of clinical diagnoses. Alzheimer's has a 20% misdiagnosis rate.

AD pathology is primarily characterized by the presence of amyloid plaques and neurofibrillary tangles. Plaques are made up of small peptides, typically 39–43 amino acids in length, called amyloid beta (also written as A-beta or Aβ). Amyloid beta is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP appears to play roles in normal neuron growth, survival and post-injury repair. APP is cleaved into smaller fragments by enzymes such as gamma secretase and beta secretase. One of these fragments gives rise to fibrils of amyloid beta which can self-assemble into the dense extracellular amyloid plaques.

Parkinson's disease

Main article: Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder. It typically manifests as bradykinesia, rigidity, resting tremor and posture instability. The crude prevalence rate of PD has been reported to range from 15 per 100,000 to 12,500 per 100,000, and the incidence of PD from 15 per 100,000 to 328 per 100,000, with the disease being less common in Asian countries.

PD is primarily characterized by death of dopaminergic neurons in the substantia nigra, a region of the midbrain. The cause of this selective cell death is unknown. Notably, alpha-synuclein-ubiquitin complexes and aggregates are observed to accumulate in Lewy bodies within affected neurons. It is thought that defects in protein transport machinery and regulation, such as RAB1, may play a role in this disease mechanism. Impaired axonal transport of alpha-synuclein may also lead to its accumulation in Lewy bodies. Experiments have revealed reduced transport rates of both wild-type and two familial Parkinson's disease-associated mutant alpha-synucleins through axons of cultured neurons. Membrane damage by alpha-synuclein could be another Parkinson's disease mechanism.

The main known risk factor is age. Mutations in genes such as α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), glucocerebrosidase (GBA), and tau protein (MAPT) can also cause hereditary PD or increase PD risk. While PD is the second most common neurodegenerative disorder, problems with diagnoses still persist. Problems with the sense of smell is a widespread symptom of Parkinson's disease (PD), however, some neurologists question its efficacy as a diagnostic tool. This assessment method is a source of controversy among medical professionals. The gut microbiome might play a role in the diagnosis of PD, and research suggests various ways that could revolutionize the future of PD treatment.

Huntington's disease

Main article: Huntington's disease

Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by mutations in the huntingtin gene (HTT). HD is characterized by loss of medium spiny neurons and astrogliosis. The first brain region to be substantially affected is the striatum, followed by degeneration of the frontal and temporal cortices. The striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder, notably chorea. Huntington's disease presents itself later in life even though the proteins that cause the disease works towards manifestation from their early stages in the humans affected by the proteins. Along with being a neurodegenerative disorder, HD has links to problems with neurodevelopment.

HD is caused by polyglutamine tract expansion in the huntingtin gene, resulting in the mutant huntingtin. Aggregates of mutant huntingtin form as inclusion bodies in neurons, and may be directly toxic. Additionally, they may damage molecular motors and microtubules to interfere with normal axonal transport, leading to impaired transport of important cargoes such as BDNF. Huntington's disease currently has no effective treatments that would modify the disease.

Multiple sclerosis

Main article: Multiple sclerosis

Multiple sclerosis (MS) is a chronic debilitating demyelinating disease of the central nervous system, caused by an autoimmune attack resulting in the progressive loss of myelin sheath on neuronal axons. The resultant decrease in the speed of signal transduction leads to a loss of functionality that includes both cognitive and motor impairment depending on the location of the lesion. The progression of MS occurs due to episodes of increasing inflammation, which is proposed to be due to the release of antigens such as myelin oligodendrocyte glycoprotein, myelin basic protein, and proteolipid protein, causing an autoimmune response. This sets off a cascade of signaling molecules that result in T cells, B cells, and macrophages crossing the blood-brain barrier and attacking myelin on neuronal axons leading to inflammation. Further release of antigens drives subsequent degeneration causing increased inflammation. Multiple sclerosis presents itself as a spectrum based on the degree of inflammation, a majority of patients experience early relapsing and remitting episodes of neuronal deterioration following a period of recovery. Some of these individuals may transition to a more linear progression of the disease, while about 15% of others begin with a progressive course on the onset of multiple sclerosis. The inflammatory response contributes to the loss of the grey matter, and as a result current literature devotes itself to combatting the auto-inflammatory aspect of the disease. While there are several proposed causal links between EBV and the HLA-DRB1*15:01 allele to the onset of MS – they may contribute to the degree of autoimmune attack and the resultant inflammation – they do not determine the onset of MS.

Amyotrophic lateral sclerosis

Main article: Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), commonly referred to Lou Gehrig's disease, is a rare neurodegenerative disorder characterized by the gradual loss of both upper motor neurons (UMNs) and lower motor neurons (LMNs). Although initial symptoms may vary, most patients develop skeletal muscle weakness that progresses to involve the entire body. The precise etiology of ALS remains unknown. In 1993, missense mutations in the gene encoding the antioxidant enzyme superoxide dismutase 1 (SOD1) were discovered in a subset of patients with familial ALS. More recently, TAR DNA-binding protein 43 (TDP-43) and Fused in Sarcoma (FUS) protein aggregates have been implicated in some cases of the disease, and a mutation in chromosome 9 (C9orf72) is thought to be the most common known cause of sporadic ALS. Early diagnosis of ALS is harder than with other neurodegenerative diseases as there are no highly effective means of determining its early onset. Currently, there is research being done regarding the diagnosis of ALS through upper motor neuron tests. The Penn Upper Motor Neuron Score (PUMNS) consists of 28 criteria with a score range of 0–32. A higher score indicates a higher level of burden present on the upper motor neurons. The PUMNS has proven quite effective in determining the burden that exists on upper motor neurons in affected patients.

Independent research provided in vitro evidence that the primary cellular sites where SOD1 mutations act are located on astrocytes. Astrocytes then cause the toxic effects on the motor neurons. The specific mechanism of toxicity still needs to be investigated, but the findings are significant because they implicate cells other than neuron cells in neurodegeneration.

Batten disease

Main article: Batten disease

Batten disease is a rare and fatal recessive neurodegenerative disorder that begins in childhood. Batten disease is the common name for a group of lysosomal storage disorders known as neuronal ceroid lipofuscinoses (NCLs) – each caused by a specific gene mutation, of which there are thirteen. Since Batten disease is quite rare, its worldwide prevalence is about 1 in every 100,000 live births. In North America, NCL3 disease (juvenile NCL) typically manifests between the ages of 4 and 7. Batten disease is characterized by motor impairment, epilepsy, dementia, vision loss, and shortened lifespan. A loss of vision is common first sign of Batten disease. Loss of vision is typically preceded by cognitive and behavioral changes, seizures, and loss of the ability to walk. It is common for people to establish cardiac arrhythmias and difficulties eating food as the disease progresses. Batten disease diagnosis depends on a conflation of many criteria: clinical signs and symptoms, evaluations of the eye, electroencephalograms (EEG), and brain magnetic resonance imaging (MRI) results. The diagnosis provided by these results are corroborated by genetic and biochemical testing. It is only in recent years that more models have been created to expedite the research process for methods to treat Batten disease.

Creutzfeldt–Jakob disease

Main article: Creutzfeldt-Jakob disease

Creutzfeldt–Jakob disease (CJD) is a prion disease that is characterized by rapidly progressive dementia. Misfolded proteins called prions aggregate in brain tissue leading to nerve cell death. Variant Creutzfeldt–Jakob disease (vCJD) is the infectious form that comes from the meat of a cow that was infected with bovine spongiform encephalopathy, also called mad cow disease.

Risk factors

Aging

Further information: Aging brain

The greatest risk factor for neurodegenerative diseases is aging. Mitochondrial DNA mutations as well as oxidative stress both contribute to aging. Many of these diseases are late-onset, meaning there is some factor that changes as a person ages for each disease. One constant factor is that in each disease, neurons gradually lose function as the disease progresses with age. It has been proposed that DNA damage accumulation provides the underlying causative link between aging and neurodegenerative disease. About 20–40% of healthy people between 60 and 78 years old experience discernable decrements in cognitive performance in several domains including working, spatial, and episodic memory, and processing speed.

Infections

Risks from viral exposures according to one biobank study

A study using electronic health records indicates that 45 (with 22 of these being replicated with the UK Biobank) viral exposures can significantly elevate risks of neurodegenerative disease, including up to 15 years after infection.

Mechanisms

Genetics

See also: Trinucleotide repeat disorder and Epigenetics of neurodegenerative diseases

Many neurodegenerative diseases are caused by genetic mutations, most of which are located in completely unrelated genes. In many of the different diseases, the mutated gene has a common feature: a repeat of the CAG nucleotide triplet. CAG codes for the amino acid glutamine. A repeat of CAG results in a polyglutamine (polyQ) tract. Diseases associated with such mutations are known as trinucleotide repeat disorders.

Polyglutamine repeats typically cause dominant pathogenesis. Extra glutamine residues can acquire toxic properties through a variety of ways, including irregular protein folding and degradation pathways, altered subcellular localization, and abnormal interactions with other cellular proteins. PolyQ studies often use a variety of animal models because there is such a clearly defined trigger – repeat expansion. Extensive research has been done using the models of nematode (C. elegans), and fruit fly (Drosophila), mice, and non-human primates.

Nine inherited neurodegenerative diseases are caused by the expansion of the CAG trinucleotide and polyQ tract, including Huntington's disease and the spinocerebellar ataxias.

Epigenetics

The presence of epigenetic modifications for certain genes has been demonstrated in this type of pathology. An example is FKBP5 gene, which progressively increases its expression with age and has been related to Braak staging and increased tau pathology both in vitro and in mouse models of AD.

Protein misfolding

See also: Stress granule

Several neurodegenerative diseases are classified as proteopathies as they are associated with the aggregation of misfolded proteins. Protein toxicity is one of the key mechanisms of many neurodegenrative diseases.

• alpha-synuclein: can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Alpha-synuclein is the primary structural component of Lewy body fibrils. In addition, an alpha-synuclein fragment, known as the non-Abeta component (NAC), is found in amyloid plaques in Alzheimer's disease.
• tau: hyperphosphorylated tau protein is the main component of neurofibrillary tangles in Alzheimer's disease; tau fibrils are the main component of Pick bodies found in behavioral variant frontotemporal dementia.
• amyloid beta: the major component of amyloid plaques in Alzheimer's disease.
• prion: main component of prion diseases and transmissible spongiform encephalopathy.

Intracellular mechanisms

Protein degradation pathways

Parkinson's disease and Huntington's disease are both late-onset and associated with the accumulation of intracellular toxic proteins. Diseases caused by the aggregation of proteins are known as proteopathies, and they are primarily caused by aggregates in the following structures:

• cytosol, e.g. Parkinson's and Huntington's
• nucleus, e.g. Spinocerebellar ataxia type 1 (SCA1)
• endoplasmic reticulum (ER), (as seen with neuroserpin mutations that cause familial encephalopathy with neuroserpin inclusion bodies)
• extracellularly excreted proteins, amyloid-beta in Alzheimer's disease

There are two main avenues eukaryotic cells use to remove troublesome proteins or organelles:

• ubiquitin–proteasome: protein ubiquitin along with enzymes is key for the degradation of many proteins that cause proteopathies including polyQ expansions and alpha-synucleins. Research indicates proteasome enzymes may not be able to correctly cleave these irregular proteins, which could possibly result in a more toxic species. This is the primary route cells use to degrade proteins.
  • Decreased proteasome activity is consistent with models in which intracellular protein aggregates form. It is still unknown whether or not these aggregates are a cause or a result of neurodegeneration.
• autophagy–lysosome pathways: a form of programmed cell death (PCD), this becomes the favorable route when a protein is aggregate-prone meaning it is a poor proteasome substrate. This can be split into two forms of autophagy: macroautophagy and chaperone-mediated autophagy (CMA).
  • macroautophagy is involved with nutrient recycling of macromolecules under conditions of starvation, certain apoptotic pathways, and if absent, leads to the formation of ubiquinated inclusions. Experiments in mice with neuronally confined macroautophagy-gene knockouts develop intraneuronal aggregates leading to neurodegeneration.
  • chaperone-mediated autophagy defects may also lead to neurodegeneration. Research has shown that mutant proteins bind to the CMA-pathway receptors on lysosomal membrane and in doing so block their own degradation as well as the degradation of other substrates.

Membrane damage

Damage to the membranes of organelles by monomeric or oligomeric proteins could also contribute to these diseases. Alpha-synuclein can damage membranes by inducing membrane curvature, and cause extensive tubulation and vesiculation when incubated with artificial phospholipid vesicles. In addition, oligomeric α-synuclein species can form nanoscale pores in lipid membranes, further contributing to membrane disruption. The tubes formed from these lipid vesicles consist of both micellar as well as bilayer tubes. Extensive induction of membrane curvature is deleterious to the cell and would eventually lead to cell death. Apart from tubular structures, alpha-synuclein can also form lipoprotein nanoparticles similar to apolipoproteins.

Mitochondrial dysfunction

The most common form of cell death in neurodegeneration is through the intrinsic mitochondrial apoptotic pathway. This pathway controls the activation of caspase-9 by regulating the release of cytochrome c from the mitochondrial intermembrane space. Reactive oxygen species (ROS) are normal byproducts of mitochondrial respiratory chain activity. ROS concentration is mediated by mitochondrial antioxidants such as manganese superoxide dismutase (SOD2) and glutathione peroxidase. Over production of ROS (oxidative stress) is a central feature of all neurodegenerative disorders. In addition to the generation of ROS, mitochondria are also involved with life-sustaining functions including calcium homeostasis, PCD, mitochondrial fission and fusion, lipid concentration of the mitochondrial membranes, and the mitochondrial permeability transition. Mitochondrial disease leading to neurodegeneration is likely, at least on some level, to involve all of these functions.

There is strong evidence that mitochondrial dysfunction and oxidative stress play a causal role in neurodegenerative disease pathogenesis, including in four of the more well known diseases Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis.

Neurons are particularly vulnerable to oxidative damage due to their strong metabolic activity associated with high transcription levels, high oxygen consumption, and weak antioxidant defense.

DNA damage

The brain metabolizes as much as a fifth of consumed oxygen, and reactive oxygen species produced by oxidative metabolism are a major source of DNA damage in the brain. Damage to a cell's DNA is particularly harmful because DNA is the blueprint for protein production and unlike other molecules it cannot simply be replaced by re-synthesis. The vulnerability of post-mitotic neurons to DNA damage (such as oxidative lesions or certain types of DNA strand breaks), coupled with a gradual decline in the activities of repair mechanisms, could lead to accumulation of DNA damage with age and contribute to brain aging and neurodegeneration. DNA single-strand breaks are common and are associated with the neurodegenerative disease ataxia-oculomotor apraxia. Increased oxidative DNA damage in the brain is associated with Alzheimer's disease and Parkinson's disease. Defective DNA repair has been linked to neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Cockayne syndrome, Parkinson's disease and xeroderma pigmentosum.

Axonal transport

Main article: Axonal transport

Axonal swelling, and axonal spheroids have been observed in many different neurodegenerative diseases. This suggests that defective axons are not only present in diseased neurons, but also that they may cause certain pathological insult due to accumulation of organelles. Axonal transport can be disrupted by a variety of mechanisms including damage to: kinesin and cytoplasmic dynein, microtubules, cargoes, and mitochondria. When axonal transport is severely disrupted a degenerative pathway known as Wallerian-like degeneration is often triggered.

Programmed cell death

Programmed cell death (PCD) is death of a cell in any form, mediated by an intracellular program. This process can be activated in neurodegenerative diseases including Parkinson's disease, amytrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. PCD observed in neurodegenerative diseases may be directly pathogenic; alternatively, PCD may occur in response to other injury or disease processes.

Apoptosis (type I)

Apoptosis is a form of programmed cell death in multicellular organisms. It is one of the main types of programmed cell death (PCD) and involves a series of biochemical events leading to a characteristic cell morphology and death.

• Extrinsic apoptotic pathways: Occur when factors outside the cell activate cell surface death receptors (e.g., Fas) that result in the activation of caspases-8 or -10.
• Intrinsic apoptotic pathways: Result from mitochondrial release of cytochrome c or endoplasmic reticulum malfunctions, each leading to the activation of caspase-9. The nucleus and Golgi apparatus are other organelles that have damage sensors, which can lead the cells down apoptotic pathways.

Caspases (cysteine-aspartic acid proteases) cleave at very specific amino acid residues. There are two types of caspases: initiators and effectors. Initiator caspases cleave inactive forms of effector caspases. This activates the effectors that in turn cleave other proteins resulting in apoptotic initiation.

Autophagic (type II)

Autophagy is a form of intracellular phagocytosis in which a cell actively consumes damaged organelles or misfolded proteins by encapsulating them into an autophagosome, which fuses with a lysosome to destroy the contents of the autophagosome. Because many neurodegenerative diseases show unusual protein aggregates, it is hypothesized that defects in autophagy could be a common mechanism of neurodegeneration.

Cytoplasmic (type III)

PCD can also occur via non-apoptotic processes, also known as Type III or cytoplasmic cell death. For example, type III PCD might be caused by trophotoxicity, or hyperactivation of trophic factor receptors. Cytotoxins that induce PCD can cause necrosis at low concentrations, or aponecrosis (combination of apoptosis and necrosis) at higher concentrations. It is still unclear exactly what combination of apoptosis, non-apoptosis, and necrosis causes different kinds of aponecrosis.

Transglutaminase

Transglutaminases are human enzymes ubiquitously present in the human body and in the brain in particular.

The main function of transglutaminases is bind proteins and peptides intra- and intermolecularly, by a type of covalent bonds termed isopeptide bonds, in a reaction termed transamidation or crosslinking.

Transglutaminase binding of these proteins and peptides make them clump together. The resulting structures are turned extremely resistant to chemical and mechanical disruption.

Most relevant human neurodegenerative diseases share the property of having abnormal structures made up of proteins and peptides.

Each of these neurodegenerative diseases have one (or several) specific main protein or peptide. In Alzheimer's disease, these are amyloid-beta and tau. In Parkinson's disease, it is alpha-synuclein. In Huntington's disease, it is huntingtin.

Transglutaminase substrates: Amyloid-beta, tau, alpha-synuclein and huntingtin have been proved to be substrates of transglutaminases in vitro or in vivo, that is, they can be bonded by trasglutaminases by covalent bonds to each other and potentially to any other transglutaminase substrate in the brain.

Transglutaminase augmented expression: It has been proved that in these neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and Huntington's disease) the expression of the transglutaminase enzyme is increased.

Presence of isopeptide bonds in these structures: The presence of isopeptide bonds (the result of the transglutaminase reaction) have been detected in the abnormal structures that are characteristic of these neurodegenerative diseases.

Co-localization: Co-localization of transglutaminase mediated isopeptide bonds with these abnormal structures has been detected in the autopsy of brains of patients with these diseases.

Management

The process of neurodegeneration is not well understood, so the diseases that stem from it have, as yet, no cures.

Animal models in research

In the search for effective treatments (as opposed to palliative care), investigators employ animal models of disease to test potential therapeutic agents. Model organisms provide an inexpensive and relatively quick means to perform two main functions: target identification and target validation. Together, these help show the value of any specific therapeutic strategies and drugs when attempting to ameliorate disease severity. An example is the drug Dimebon by Medivation, Inc. In 2009 this drug was in phase III clinical trials for use in Alzheimer's disease, and also phase II clinical trials for use in Huntington's disease. In March 2010, the results of a clinical trial phase III were released; the investigational Alzheimer's disease drug Dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease. With CONCERT, the remaining Pfizer and Medivation Phase III trial for Dimebon (latrepirdine) in Alzheimer's disease failed in 2012, effectively ending the development in this indication.

In another experiment using a rat model of Alzheimer's disease, it was demonstrated that systemic administration of hypothalamic proline-rich peptide (PRP)-1 offers neuroprotective effects and can prevent neurodegeneration in hippocampus amyloid-beta 25–35. This suggests that there could be therapeutic value to PRP-1.

Other avenues of investigation

Protein degradation offers therapeutic options both in preventing the synthesis and degradation of irregular proteins. There is also interest in upregulating autophagy to help clear protein aggregates implicated in neurodegeneration. Both of these options involve very complex pathways that we are only beginning to understand.

The goal of immunotherapy is to enhance aspects of the immune system. Both active and passive vaccinations have been proposed for Alzheimer's disease and other conditions; however, more research must be done to prove safety and efficacy in humans.

A current therapeutic target for the treatment of Alzheimer's disease is the protease β-secretase, which is involved in the amyloidogenic processing pathway that leads to the pathological accumulation of proteins in the brain. When the gene that encodes for amyloid precursor protein (APP) is spliced by α-secretase rather than β-secretase, the toxic protein β amyloid is not produced. Targeted inhibition of β-secretase can potentially prevent the neuronal death that is responsible for the symptoms of Alzheimer's disease.