Apr 11, 2015 prion like seeding and propagation of taupathology have been demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative tauopathies. They suggest a general pathogenic mechanism for other neurodegenerative diseases linked to fibrillar protein aggregation. Apr, 2017 a wealth of evidence has emerged within the last decade to suggest that the misfolded tau in tauopathies possesses prion like features, and that such features may explain the diverse features of tauopathies. Alternative splicing of the tau gene gives rise to 6 tau isoforms that differ by the absence or presence of 1 or 2 nterminal inserts n in combination with either 3 3r tau or 4 repeats 4r tau domains in the cterminal region that constitute the microtubule binding domains. The prion like characteristics of tau are relevant to two key features of tauopathy. Until recently, the events leading to aggregate formation were believed to be entirely cellautonomous, with protein misfolding occurring independently in. This soluble hyperphosphorylated tau is, however, clearly distinct from aggregated fibrillary tau in neurofibrillary tangles, despite both being implicated in tau toxicity. Jun 18, 2019 formation and aggregation of misfolded proteins in the central nervous system cns is a key hallmark of several agerelated neurodegenerative diseases, including parkinsons disease pd, alzheimers disease ad, and amyotrophic lateral sclerosis als. Whether prion like transmission mechanisms actively contribute to the pathogenesis of idiopathic neurodegenerative diseases remains unclear. Prionlike properties of assembled tau protein request pdf. The progressive development of alzheimers disease ad pathology follows a spatiotemporal pattern in the human brain. The prion hypothesis states that misfolded proteins can act as infectious agents that template the misfolding and aggregation of healthy proteins to transmit a disease.
A wealth of evidence has emerged within the last decade to suggest that the misfolded tau in tauopathies possesses prion like features and that such features may explain the diverse characteristics of tauopathies. Prionlike spreading of alzheimers disease within the. The prion like concept for tauopathies arose initially from the observation that the progressive accumulation of tau pathology as the. These diseases share key biophysical and biochemical characteristics with prion diseases. Tau protein liquidliquid phase separation can initiate tau. However, even in this extreme example of lossoffunction in a prion like disease, both gain and lossoffunction mechanisms work together to propagate disease. For example, the tau pathology in corticobasal degeneration is distinct from that of an ad patient. Cosmin stancu1 bruno vasconcelos1 laurence ris2 peng wang1 agnes villers 2 eve peeraer3 arjan buist3 dick terwel4 peter baatsen5.
Frontiers prionlike mechanisms in parkinsons disease. Prions stably propagate unique conformations strains that produce different pathologies. Sep 14, 2014 read prion like mechanisms in the pathogenesis of tauopathies and synucleinopathies, current neurology and neuroscience reports on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Isolated in 1975, tau was described as a heat stable protein that controls the polymerization of microtubules. Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion like manner. The prionlike concept for tauopathies arose initially from the observation that the progressive accumulation of tau pathology as the. We conclude that prionlike propagation of sod1 misfolding in als has an unambiguous and substantial lossoffunction component in its etiology. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. However, even in this extreme example of lossoffunction in a prionlike disease, both gain and lossoffunction mechanisms work together to propagate disease. Prionlike templated misfolding in tauopathies request pdf. The misfolding and aggregation of specific proteins within nervous system occur in most ageassociated neurodegenerative diseases including alzheimers disease ad. Sheet core of tau paired helical filaments revealed by. Tau is an exceptionally soluble protein, and the molecular mecha.
There is increasing experimental evidence implicating prionlike mechanisms in many common neurodegenerative disorders, including alzheimer disease, parkinson disease, the tauopathies, and amyotrophic lateral sclerosis als, all of which feature the aberrant misfolding and aggregation of. Protein aggregation of prionlike features of misfolded ab. Finally, such new ways of thinking have led to different therapeutic strategies in antitau immunotherapy among tauopathies and have stimulated. Prionlike seeding and propagation of taupathology have been demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative tauopathies. We conclude that prion like propagation of sod1 misfolding in als has an unambiguous and substantial lossoffunction component in its etiology. These studies have convincingly demonstrated that a. Prionlike properties of tau assemblies sciencedirect. All of this evidence, and other examples of similar prion like behaviors, e. We cannot exclude that diseaserelated proteins transfer between individuals through the use of contaminated surgical tools or on tissue transplant, but there are no reports to support this. The fuzzy coat of pathological human tau fibrils is a twolayered polyelectrolyte brush. In 1975, a protein was isolated from brain and named tau because of its ability to induce microtubule formation 100. Here we analyzed the repercussions of prionlike spreading.
Animal models for prionlike diseases sciencedirect. Prion disease is unique in that the natively folded prion protein forms diverse misfolded aggregates with distinct molecular conformations strains, which underlie different disease phenotypes. In nerve cells, tau is concentrated in axons 8, but it may also have a physiological function in dendrites 52. Alzheimers disease, alphasynuclein, parkinsons disease, prionlike, tau.
Prionlike transmission of pathogenic protein aggregates. Although the major protein component of the pathological aggregations can be unique for each neurodegenerative disease e. Moreover, the data demonstrate that different conformations can occur in different pathological settings and therefore imply that these conformations might account for the different clinical and neuropathological characteristics of the various tauopathies. Prions induce templated misfolding of a normal prion protein, the propagation of this misfolding in the brain, across tissues e. This article described the prionlike features of proteins, the similarities with bona. Stancu ic, vasconcelos b, ris l, wang p, villers a, peeraer e, et al. Like templated misfolding in tauopathies, brain pathology on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Dec 23, 2009 recent studies have highlighted prion like mechanisms of propagation of protein misfolding in various common, noninfectious neurodegenerative diseases those in which transmission between. Like templated misfolding in tauopathies wiley online.
Prionlike mechanisms in the pathogenesis of tauopathies and synucleinopathies. The proteopathies also known as proteinopathies, protein conformational disorders, or protein misfolding diseases include such diseases as creutzfeldtjakob disease and other prion diseases, alzheimers disease, parkinsons disease, amyloidosis, multiple system atrophy, and a wide range of other disorders see list of proteopathies. Protein misfolding and accumulation in neurodegeneration a common feature of neurodegenerative diseases is the presence of misfolded protein aggregates in affected regions of the nervous system. Propagation of protein misfolding in these diseases may therefore occur through. Removing endogenous tau does not prevent tau propagation yet. In a transgenic tg mouse model of ad expressing amyloid precursor protein app with the arctic e693g mutation, pathology spreads along anatomically connected structures. A wealth of evidence has emerged within the last decade to suggest that the misfolded tau in tauopathies possesses prionlike features, and that such features may explain the diverse features of tauopathies. Isoform compositions and morphologies of tau filaments can differ between tauopathies, which is consistent with the existence of distinct tau strains. Here we analyzed the repercussions of prion like spreading of taupathology via. Recent studies have highlighted prionlike mechanisms of propagation of protein misfolding in various common, noninfectious neurodegenerative diseases those in. Prion diseases belong to the group of protein misfolding neurodegenerative diseases. Direct and indirect evidence for interneuronal tau transmission in animal models suggests that the transfer of toxic tau species between neurons might be caused by the interneuronal spreading of.
What is the evidence that tau pathology spreads through. However, the involvement of templated misfolding of tau in neuronal network dysfunction and behavioral outcomes remains to be explored in detail. Formation and aggregation of misfolded proteins in the central nervous system cns is a key hallmark of several agerelated neurodegenerative diseases, including parkinsons disease pd, alzheimers disease ad, and amyotrophic lateral sclerosis als. Templated misfolding of tau by prionlike seeding along neuronal connections impairs.
Propagation of tau misfolding from the outside to the inside of a cell. The central concept is of selfpropagating misfolded proteins spreading from neuron to neuron, associated with more or less stereotypical patterns of neurodegeneration in specific diseases. The cell biology of prionlike spread of protein aggregates. Human prion diseases are rare, but they are serious, causing progressive brain damage that results in patients eventually losing their ability to speak or move. Prionlike behaviour of tau for now is mainly documented by templated seeding and propagation of aggregation across brain areas. All of this evidence, and other examples of similar prionlike behaviors, e. The contribution of selective vulnerability of neuronal populations, as an alternative to prionlike mechanisms to explain spreading of tau pathology needs to be clarified. Feb 15, 2018 a wealth of evidence has emerged within the last decade to suggest that the misfolded tau in tauopathies possesses prion like features, and that such features may explain the diverse features of tauopathies. Prion basics human diseases like animal prion diseases, human prion diseases involve misfolded prion proteins and the death of brain cells. Frontiers diverse misfolded conformational strains and. Prionlike mechanisms in the pathogenesis of tauopathies. Prionlike mechanisms in neurodegenerative diseases. Prions are selfreplicating protein aggregates and are the primary causativefactor in a number of neurological diseases in mammals.
Tau propagation, different tau phenotypes, and prionlike. What is the evidence that tau pathology spreads through prionlike. Prion like seeding and propagation of taupathology have been demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative tauopathies. Emerging experimental evidence suggests that the spread of tau pathology in the brain in tauopathies reflects the propagation of abnormal tau species along neuroanatomically connected brain areas. Mechanisms of secretion and spreading of pathological tau.
Brain homogenates from human tauopathies were intracerebrally injected into mice transgenic for human wildtype tau, where they induced the formation of silverpositive tau inclusions. Cellular models of aggregationdependent templatedirected. Protein misfolding underlies many neurodegenerative diseases including tauopathies, where the misfolded tau protein propagates pathology through connected brain circuits in a prionlike manner. Removing endogenous tau does not prevent tau propagation. From the prionlike propagation hypothesis to therapeutic. Increasing evidence suggests that pathological proteins in neurodegenerative diseases adopt prionlike mechanisms and spread across the brain along anatomically connected networks. First, in alzheimers disease, the progression of tau aggregation follows stereotypical anatomical. Recent studies have highlighted prionlike mechanisms of propagation of protein misfolding in various common, noninfectious neurodegenerative diseases those in which transmission between. Like prions, tau strains are true to form alzforum. Reconsidering a required role for protein lossoffunction patricia l. Protein misfolding, aggregation, and conformational strains. Prionlike characteristics of the microtubuleassociated.
Significance statement public awareness of progressive neurodegenerations such as dementias associated with aging or repetitive head trauma is rising. Whether prionlike transmission mechanisms actively contribute to the pathogenesis of idiopathic neurodegenerative diseases remains unclear. Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as alzheimers disease and frontotemporal lobar degeneration. Moreover, misfolded protein aggregates can promote misfolding and aggregation of different. Thus, despite the fact that infectious prion diseases are clearly zoonoses and there is no evidence that ad, pd, and related synucleinopathies, a. Pdf prionlike mechanisms in neurodegenerative diseases. Here we analyzed the repercussions of prionlike spreading of taupathology via. A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. Pathogens free fulltext prions and prionlike pathogens. Diverse misfolded conformational strains and cross. Numerous neurodegenerative diseases including prion, alzheimers and parkinsons diseases are characterized by accumulation of protein aggregates in brain. The prionlike concept for tauopathies arose initially from the observation that the. The importance of extracellular tau as a therapeutic target j biol chem 2014 289. Tauopathies constitute neurodegenerative diseases that are characterized by the intracellular deposition of.
Sep 14, 2014 neurodegenerative diseases, including alzheimers disease and parkinsons disease, are characterized by the abnormal aggregation of a small number of intracellular proteins, with tau and. Prionlike mechanisms in alzheimers disease bentham science. Sep 24, 2018 a hallmark event in neurodegenerative diseases nds is the misfolding, aggregation, and accumulation of proteins, leading to cellular dysfunction, loss of synaptic connections, and brain damage. Clavaguera f, lavenir i, falcon b, frank s, goedert m, tolnay m. Templated misfolding of tau by prionlike seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in tau transgenic mice. Prionlike mechanisms in neurodegenerative diseases nature. Templated misfolding of tau by prionlike seeding along. Protein misfolding in prion and prionlike diseases. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby.
Many tau inclusions survive the death of affected nerve cells as extracellular or ghost tangles. In tauopathies such as alzheimers disease, this model predicts that tau seeds propagate pathol. The implications of these findings are discussed with. Lesion of the subiculum reduces the spread of amyloid beta. The prionlike behavior of assembled tau in transgenic mice. What is the evidence that tau pathology spreads through prion. Prionlike mechanisms in the pathogenesis of tauopathies and. A wealth of evidence has emerged within the last decade to suggest that the misfolded tau in tauopathies possesses prionlike features and that such features may explain the diverse characteristics of tauopathies. Measurement of tau filament fragmentation provides insights. The prionlike nature of neurodegenerative diseases has been mooted for a number of years. The propagation of prionlike protein inclusions in. Like templated misfolding in tauopathies clavaguera. From the tanz centre for research in neurodegenerative diseases and the department of medical biophysics, university of toronto, toronto, ontario m5t 2s8. Tau misfolding efficiently propagates between individual.
From the prionlike propagation hypothesis to therapeutic strategies. Read prionlike mechanisms in the pathogenesis of tauopathies and synucleinopathies, current neurology and neuroscience reports on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Prionlike transmission of pathogenic protein aggregates in genetic models of neurodegenerative disease. All such studies are most consistent with the idea that pathology results from templated seeding reactions in vivo. Another example of templated misfolding of tau seems to occur in the observed.
Alzheimers disease, other conditions linked to prionlike. Pdf templated misfolding of tau by prionlike seeding. Tauopathies are neurodegenerative diseases characterized by. Prionlike spread of protein aggregates in neurodegeneration. This propagation could occur through a prionlike mechanism involving transfer of abnormal tau seeds from a donor cell to a recipient cell and recruitment of normal tau in the.
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