Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
BBA - Molecular Basis of Disease (v.1739, #2-3)
Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases by Athena Andreadis (pp. 91-103).
Organization of cytoskeletal elements is critical for cellular migration and maintenance of morphology. Tau protein, which binds to and organizes microtubules, is instrumental in forming and maintaining the neuronal axon. Disturbances in tau expression result in disruption of the neuronal cytoskeleton and formation of pathological tau structures (neurofibrillary tangles, NFTs) found in brains of dementia sufferers. Null tau mice, although viable, exhibit developmental and cognitive defects and transgenic mice which overexpress tau develop severe neuropathies.The neuron-specific tau transcript produces multiple isoforms by intricately regulated alternative splicing. These isoforms modulate tau function in normal brain. Moreover, aberrations in tau splicing regulation directly cause several neurodegenerative diseases. Thus, tau splicing regulation is vital to neuronal health and correct brain function.This review briefly presents our cumulative knowledge of tau splicing—cis elements and trans factors which influence it at the RNA level, its effect on the structure and roles of the tau protein and its repercussions on neuronal morphology and neurodegeneration.
Keywords: Alternative splicing; MAP tau; Neuronal structure and function; Neurodegeneration
Regulation of tau isoform expression and dementia by Ian D'Souza; Gerard D. Schellenberg (pp. 104-115).
In the central nervous system (CNS), aberrant changes in tau mRNA splicing and consequently in protein isoform ratios cause abnormal aggregation of tau and neurodegeneration. Pathological tau causes neuronal loss in Alzheimer's disease (AD) and a diverse group of disorders called the frontotemporal dementias (FTD), which are two of the most common forms of dementia and afflict more than 10% of the elderly population. Autosomal dominant mutations in the tau gene cause frontotemporal dementia with parkinsonism-chromosome 17 type (FTDP-17). Just over half the mutations affect tau protein function and decrease its affinity for microtubules (MTs) or increase self-aggregation. The remaining mutations occur within exon 10 (E10) and intron 10 sequences and alter complex regulation of E10 splicing by multiple mechanisms. FTDP-17 splicing mutations disturb the normally balanced levels of distinct protein isoforms that result in altered biochemical and structural properties of tau. In addition to FTDP-17, altered tau isoform levels are also pathogenically associated with other FTD disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration and Pick's disease; however, the mechanisms remain undefined and mutations in tau have not been detected. FTDP-17 highlights the association between splicing mutations and the pronounced variability in pathology as well as phenotype that is characteristic of inherited disorders.
Keywords: Tau; Dementia
Cultured cell and transgenic mouse models for tau pathology linked to β-amyloid by George S. Bloom; Ke Ren; Charles G. Glabe (pp. 116-124).
The two histopathological signatures of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles, prompting speculation that a causal relationship exists between the respective building blocks of these abnormal brain structures: the β-amyloid peptides (Aβ) and the neuron-enriched microtubule-associated protein called tau. Transgenic mouse models have provided in vivo evidence for such connections, and cultured cell models have allowed tightly controlled, systematic manipulation of conditions that influence links between Aβ and tau. The emerging evidence supports the view that amyloid pathology lies upstream of tau pathology in a pathway whose details remain largely mysterious. In this communication, we review and discuss published work about the Aβ–tau connection. In addition, we present some of our own previously unpublished data on the effects of exogenous Aβ on primary brain cultures that contain both neurons and glial cells. We report here that continuous exposure to 5 μM non-fibrillar Aβ40 or Aβ42 kills primary brain cells by apoptosis within 2–3 weeks, Aβ42 is more toxic and selective for neurons than Aβ40, and Aβ42, but not Aβ40, induces a transient increase in neurons that are positive for the AD-like PHF1 epitope. These findings demonstrate the greater potency of Aβ42 than Aβ40 at inducing tau pathology and programmed cell death, and corroborate and extend reports that tau-containing cells are more sensitive to Aβ peptides than cells that lack or express low levels of tau.
Keywords: Alzheimer's disease; Tauopathies; Apoptosis; Primary brain culture
Recent advances in experimental modeling of the assembly of tau filaments by Li-wen Ko; Michael DeTure; Naruhiko Sahara; Rifki Chihab; Irving E. Vega; Shu-Hui Yen (pp. 125-139).
Intracellular assembly of microtubule-associated protein tau into filamentous inclusions is central to Alzheimer's disease and related disorders collectively known as tauopathies. Although tau mutations, posttranslational modifications and degradations have been the focus of investigations, the mechanism of tau fibrillogenesis in vivo still remains elusive. Different strategies have been undertaken to generate animal and cellular models for tauopathies. Some are used to study the molecular events leading to the assembly and accumulation of tau filaments, and others to identify potential therapeutic agents that are capable of impeding tauopathy. This review highlights the latest developments in new models and how their utility improves our understanding of the sequence of events leading to human tauopathy.
Keywords: Cellular model; Conditional transfectant; Tau aggregation; Tauopathy
Potential structure/function relationships of predicted secondary structural elements of tau by T. Chris Gamblin (pp. 140-149).
The microtubule-associated protein tau is believed to be a natively unfolded molecule with virtually no secondary structure. However, this protein self-associates into filamentous forms in various neurodegenerative diseases. Since these filamentous forms show a remarkable degree of higher order due to their regular widths and periodicity, it is widely speculated that tau does contain secondary structures that come together to form tertiary and quaternary structures in the filamentous form. The purpose of this review is to use the primary sequence of tau along with predictive methods in an effort to identify potential secondary structural elements that could be involved in its normal and pathological functions. Although there are few predicted structural elements in the tau molecule, these analyses should lead to a better understanding of the structure/function relationships that regulate the behavior of tau.
Keywords: Tau; Alzheimer's disease; Paired helical filament; Protein structure; Sequence analysis; Polymerization
Transcriptional and conformational changes of the tau molecule in Alzheimer's disease by Bradley T. Hyman; Jean C. Augustinack; Martin Ingelsson (pp. 150-157).
Mutations in the tau gene cause frontotemporal dementia with parkinsonism, presumably by affecting the balance between tau isoforms (with either three or four microtubule-binding repeats) or by impairing tau-tubulin binding. Although to date no mutations have been found for Alzheimer's disease, it is plausible that tangle pathology in this disorder is also driven by similar molecular modifications. Investigations of Alzheimer brain tissue with new technologies such as laser capture microscopy, quantitative PCR and fluorescence lifetime imaging will shed light on whether transcriptional or conformational alterations play a role in Alzheimer pathogenesis.
Keywords: Tau; Microtubule; Alternative splicing; qPCR; Conformational changes; FRET
Tau aggregation is driven by a transition from random coil to beta sheet structure by Martin von Bergen; Stefan Barghorn; Jacek Biernat; Eva-Maria Mandelkow; Eckhard Mandelkow (pp. 158-166).
The abnormal aggregation of the microtubule associated protein tau into paired helical filaments (PHFs) is one the hallmarks of Alzheimer's disease. The soluble protein is one of the longest natively unfolded proteins, lacking significant amounts of secondary structure over a sequence of 441 amino acids in the longest isoform. Furthermore, the unfolded character is consistent with some notable features of the protein like stability towards heat and acid treatment. It is still unclear how these characteristics support the physiological function of binding to and stabilization of microtubules. We review here some recent studies on how an unfolded protein such as tau can adopt β-structure, which then leads to the highly ordered morphology of the PHFs. The core sequence for both microtubule binding and PHF formation is the microtubule binding domain containing three or four repeats. This region alone is sufficient for PHF formation and mostly unfolded in the soluble state. A search for sequence motifs within this region crucial for PHF building revealed two hexapeptides in the second and the third repeat. Some of the genetically linked cases of FTDP-17 show missense mutations in or adjacent to these hexapeptide motifs. Proteins containing the P301L and the ΔK280 mutations exhibit accelerated aggregation. The importance of the two hexapeptides stems from their capacity to undergo a conformational change from a random coil to a beta sheet structure. The increase of beta sheet structure is a typical feature of an amyloidogenic protein and is the basis of other characteristics like a decreased sensitivity towards proteolytic degradation and Congo red binding. PHFs aggregated in vitro and in vivo contain β-sheet structure, as judged by circular dichroism (CD) spectroscopy, Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction.
Keywords: Abbreviations; AD; Alzheimer's disease; APP; amyloid precursor protein; CD; circular dichroism; EM; electron microscope; FTIR; Fourier transform infrared; PHF; paired helical filaments; ThS; thioflavin SAlzheimer's disease; Tau; Paired helical filament; FTDP-17; Cross beta structure
Pathways of tau fibrillization by Jeff Kuret; Carmen N. Chirita; Erin E. Congdon; Theresa Kannanayakal; Guibin Li; Mihaela Necula; Haishan Yin; Qi Zhong (pp. 167-178).
New methods for analyzing tau fibrillization have yielded insights into the biochemical transitions involved in the process. Here we review the parallels between the sequential progression of tau fibrillization observed macroscopically in Alzheimer's disease (AD) lesions and the pathway of tau aggregation observed in vitro with purified tau preparations. In addition, pharmacological agents for further dissection of fibrillization mechanism and lesion formation are discussed.
Keywords: Alzheimer's disease; Neurofibrillary tangle; Tau; Folding intermediate; Aggregation; Kinetics
Tau protein as a differential biomarker of tauopathies by Nicolas Sergeant; André Delacourte; Luc Buée / (pp. 179-197).
Microtubule-associated Tau proteins are the basic component of intraneuronal and glial inclusions observed in many neurological disorders, the so-called tauopathies. Many etiological factors, phosphorylation, splicing, and mutations, relate Tau proteins to neurodegeneration. Molecular analysis has revealed that hyperphosphorylation and abnormal phosphorylation might be one of the important events in the process leading to tau intracellular aggregation. Specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution, could characterize five main classes of tauopathies. A direct correlation has been established between the regional brain distribution of tau pathology and clinical symptoms; for instance progressive involvement of neocortical areas is well correlated to the severity of dementia in Alzheimer's disease, overall suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. Recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies. Overall, a better knowledge of the etiological factors responsible for the aggregation of tau proteins in brain diseases is essential for development of future differential diagnosis and therapeutic strategies. They would hopefully find their application against Alzheimer's disease but also in all neurological disorders for which a dysfunction of Tau biology has been identified.
Keywords: Alzheimer's disease; Tauopathy; Microtubule-associated tau; Physiopathology; Biomarker
Tau pathology in Alzheimer disease and other tauopathies by Khalid Iqbal; Alejandra del C. Alonso; She Chen; M. Omar Chohan; Ezzat El-Akkad; Cheng-Xin Gong; Sabiha Khatoon; Bin Li; Fei Liu; Abdur Rahman; Hitoshi Tanimukai; Inge Grundke-Iqbal (pp. 198-210).
Just as neuronal activity is essential to normal brain function, microtubule-associated protein tau appears to be critical to normal neuronal activity in the mammalian brain, especially in the evolutionary most advanced species, the homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-associated proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathology which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathological tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathological tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau and as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.
Keywords: Neurofibrillary degeneration; Microtubule-associated protein tau; Microtubule; Microtubule-associated protein 2; Neurofilament; Memantine; Abnormal hyperphosphorylation of tau; Protein phosphatase-2A
Tau modifiers as therapeutic targets for Alzheimer's disease by Quan Liu; Hyoung-gon Lee; Kazuhiro Honda; Sandra L. Siedlak; Peggy L.R. Harris; Adam D. Cash; Xiongwei Zhu; Jesús Avila; Akihiko Nunomura; Atsushi Takeda; Mark A. Smith; George Perry (pp. 211-215).
Fibrillogenesis is a major feature of Alzheimer's disease (AD) and other neurodegenerative diseases. Fibers are correlated with disease severity and they have been implicated as playing a direct role in disease pathophysiology. In studies of tau, instead of finding causality with tau fibrils, we found that tau is associated with reduction of oxidative stress. Biochemical findings show that tau oxidative modifications are regulated by phosphorylation and that tau found in neurofibrillary tangles is oxidatively modified, suggesting that tau is closely linked to the biology, not toxicity, of AD.
Keywords: Alzheimer's disease; Heme oxygenase; 4-hydroxy-2-nonenal; Lipid peroxidation; Oxidative stress
Tau, tangles, and Alzheimer's disease by Lester I. Binder; Angela L. Guillozet-Bongaarts; Francisco Garcia-Sierra; Robert W. Berry (pp. 216-223).
Neurofibrillary tangles (NFT) are comprised of the microtubule-associated protein tau, in the form of filamentous aggregates. In addition to the well-known changes in phosphorylation state, tau undergoes multiple truncations and shifts in conformation as it transforms from an unfolded monomer to the structured polymer characteristic of NFT. Truncations at both the amino- and carboxy-termini directly influence the conformation into which the molecule folds, and hence the ability of tau to polymerize into fibrils. Certain of these truncations may be due to cleavage by caspases as part of the apoptotic cascade. In this review, we discuss evidence that strongly suggests that these truncations occur in an orderly pattern and directly influence the ability of tau to polymerize into filaments.
Keywords: Neurofibrillary tangle; Tau; Alzheimer's disease
Modeling tauopathy: a range of complementary approaches by Garth F. Hall; Jun Yao (pp. 224-239).
The large group of neurodegenerative diseases which feature abnormal metabolism and accumulation of tau protein (tauopathies) characteristically produce a multiplicity of cellular and systemic abnormalities in human patients. Understanding the complex pathogenetic mechanisms by which abnormalities in tau lead to systemic neurofibrillary degenerative disease requires the construction and use of model experimental systems in which the behavior of human tau can be analyzed under controlled conditions. In this paper, we survey the ways in which in vitro, cellular and whole-animal models of human tauopathy are being used to add to our knowledge of the pathogenetic mechanisms underlying these conditions. In particular, we focus on the complementary advantages and limitations of various approaches to constructing tauopathy models presently in use with respect to those of murine transgenic tauopathy models.
Keywords: Tauopathy; Animal model; Neurofibrillary; Neurodegeneration; Cell culture; Transgenic
Mutations causing neurodegenerative tauopathies by Michel Goedert; Ross Jakes (pp. 240-250).
Tau is the major component of the intracellular filamentous deposits that define a number of neurodegenerative diseases. They include the largely sporadic Alzheimer's disease (AD), progressive supranuclear palsy, corticobasal degeneration, Pick's disease and argyrophilic grain disease, as well as the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). For a long time, it was unclear whether the dysfunction of tau protein follows disease or whether disease follows tau dysfunction. This was resolved when mutations in Tau were found to cause FTDP-17. Currently, 32 different mutations have been identified in over 100 families. About half of the known mutations have their primary effect at the protein level. They reduce the ability of tau protein to interact with microtubules and increase its propensity to assemble into abnormal filaments. The other mutations have their primary effect at the RNA level and perturb the normal ratio of three-repeat to four-repeat tau isoforms. Where studied, this resulted in a relative overproduction of tau protein with four microtubule-binding domains in the brain. Individual Tau mutations give rise to diseases that resemble progressive supranuclear palsy, corticobasal degeneration or Pick's disease. Moreover, the H1 haplotype of Tau has been identified as a significant risk factor for progressive supranuclear palsy and corticobasal degeneration. At a practical level, the new work is leading to the production of experimental animal models that reproduce the essential molecular and cellular features of the human tauopathies, including the formation of abundant filaments made of hyperphosphorylated tau protein and nerve cell degeneration.
Keywords: Tau protein isoform; Mutation; Tau filament; Frontotemporal dementia; Parkinsonism; Tauopathy
Transgenic animal models of tauopathies by Virginia M.-Y. Lee; Theresa K. Kenyon; John Q. Trojanowski (pp. 251-259).
Tauopathies are a group of neurodegenerative disorders that include Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and other related diseases with prominent tau pathology. Research advances in the last several decades have characterized and defined tau neuropathologies of both neuron and glia in these diverse disorders and this has stimulated development of animal models of tauopathies. Indeed, animal models ranging from invertebrate species such as C. elegan to Drosophila melanogaster and mammalian transgenic mouse models of tauopathies have been generated and reported. This review summarizes the salient features of many of the known models of tauopathies.
Keywords: Tau; Tauopathy; Animal model; Frontotemporal dementia; Transgenic
Can tau filaments be both physiologically beneficial and toxic? by Michelle E. King (pp. 260-267).
Alzheimer's disease (AD) is a progressive disease of aging primarily characterized at the behavioral level by symptoms of memory loss. The pathological hallmarks of AD are extracellular plaques and intracellular neurofibrillary tangles that are composed of filamentous polymers of β-amyloid (Aβ) and tau, respectively. Aggregates of filaments are not unique to AD—fibrous polymers are the pathological signatures of many diseases of aging such as Huntington's disease and Parkinson's disease. Whether Aβ or tau filaments cause AD is still an open question, as a wide variety of proteins and pathways have been implicated in the initiation and advancement of the disease—processes such as apoptosis, oxidative stress, and protein degradation. That polymers are the prevalent species observed in aging disorders suggests that this morphology of aggregation represents a significant physiological role. As a consequence of an independent insult or aging itself, the filament shifts from a physiological role to one with pathological implications. The relative importance of Aβ filaments versus tau filaments has also been a focus of significant debate within the research community. Although genetic evidence indicates that Aβ filaments are an integral component in AD, only tau pathology has been found to correlate with symptom presentation in patients. Not only do tau filaments greatly contribute to the systematic loss of neurons and the pathological presentation of memory loss, but they may represent a physiological process whose regulation may be controlled.
Keywords: Tau filament; β-Amyloid; Alzheimer's disease
Inability of tau to properly regulate neuronal microtubule dynamics: a loss-of-function mechanism by which tau might mediate neuronal cell death by Stuart C. Feinstein; Leslie Wilson (pp. 268-279).
Interest in the microtubule-associated protein tau stems from its critical roles in neural development and maintenance, as well as its role in Alzheimer's, FTDP-17 and related neurodegenerative diseases. Under normal circumstances, tau performs its functions by binding to microtubules and powerfully regulating their stability and growing and shortening dynamics. On the other hand, genetic analyses have established a clear cause-and-effect relationship between tau dysfunction/mis-regulation and neuronal cell death and dementia in FTDP-17, but the molecular basis of tau's destructive action(s) remains poorly understood. One attractive model suggests that the intracellular accumulation of abnormal tau aggregates causes cell death, i.e., a gain-of-toxic function model. Here, we describe the evidence and arguments for an alternative loss-of-function model in which tau-mediated neuronal cell death is caused by the inability of affected cells to properly regulate their microtubule dynamic due to mis-regulation by tau. In support of this model, our recent data demonstrate that missense FTDP-17 mutations that alter amino acid residues near tau's microtubule binding region strikingly modify the ability of tau to modulate microtubule dynamics. Additional recent data from our labs support the notion that the same dysfunction occurs in the FTDP-17 regulatory mutations that alter tau RNA splicing patterns. Our model posits that the dynamics of microtubules in neuronal cells must be tightly regulated to enable them to carry out their diverse functions, and that microtubules that are either over-stabilized or under-stabilized, that is, outside an acceptable window of dynamic activity, lead to neurodegeneration. An especially attractive aspect of this model is that it readily accommodates both the structural and regulatory classes of FTDP-17 mutations.
Keywords: Tau; Microtubule dynamics; FTDP-17; Alzheimer's disease; Cytoskeleton; Loss-of-function
Tau phosphorylation: physiological and pathological consequences by William H. Stoothoff; Gail V.W. Johnson (pp. 280-297).
The microtubule-associated protein tau, abundant in neurons, has gained notoriety due to the fact that it is deposited in cells as fibrillar lesions in numerous neurodegenerative diseases, and most notably Alzheimer's disease. Regulation of microtubule dynamics is the most well-recognized function of tau, but it is becoming increasingly evident that tau plays additional roles in the cell. The functions of tau are regulated by site-specific phosphorylation events, which if dysregulated, as they are in the disease state, result in tau dysfunction and mislocalization, which is potentially followed by tau polymerization, neuronal dysfunction and death. Given the increasing evidence that a disruption in the normal phosphorylation state of tau plays a key role in the pathogenic events that occur in Alzheimer's disease and other neurodegenerative conditions, it is of crucial importance that the protein kinases and phosphatases that regulate tau phosphorylation in vivo as well as the signaling cascades that regulate them be identified. This review focuses on recent literature pertaining to the regulation of tau phosphorylation and function in cell culture and animal model systems, and the role that a dysregulation of tau phosphorylation may play in the neuronal dysfunction and death that occur in neurodegenerative diseases that have tau pathology.
Keywords: Tau; Tauopathy; Phosphorylation; Filament; Kinase; Phosphatase
Phosphorylated tau and the neurodegenerative foldopathies by Kenneth S. Kosik; Hideki Shimura (pp. 298-310).
Many studies have implicated phosphorylated tau in the Alzheimer disease process. However, the cellular fate of phosphorylated tau has only recently been described. Recent work has shown that tau phosphorylation at substrate sites for the kinases Cdk5 and GSK3-beta can trigger the binding of tau to the chaperones Hsc70 and Hsp27. The binding of phosphorylated tau to Hsc70 implied that the complex may be a substrate for the E3 ligase CHIP and this possibility was experimentally verified. The presence of this system in cells suggests that phosphorylated tau may hold toxic dangers for cell viability, and the response of the cell is to harness a variety of protective mechanisms. These include binding to chaperones, which may prevent more toxic conformations of the protein, ubiquitination which will direct the protein to the proteasome, segregation of tau aggregates from the cellular machinery, and recruitment of Hsp27 which will confer anti-apoptotic properties to the cell.
Keywords: Hsc70; Hsp27; CHIP; Cdk5 and GSK3-beta; Phosphorylated tau
Pinning down phosphorylated tau and tauopathies by Jormay Lim; Kun Ping Lu (pp. 311-322).
Neurofibrillary tangles (NFTs) are prominent neuronal lesions in a large subset of neurodegenerative diseases, including Alzheimer's disease (AD). NFTs are mainly composed of insoluble Tau that is hyperphosphorylated on many serine or threonine residues preceding proline (pSer/Thr–Pro). Tau hyperphosphorylation abolishes its biological function to bind microtubules and promotes microtubule assembly and precedes neurodegeneration. Not much is known about how tau is further regulated following phosphorylation. Notably, we have recently shown that phosphorylated Ser/Thr–Pro motifs exist in two distinct conformations. The conversion between two conformations in some proteins is catalyzed by the prolyl isomerase Pin1. Pin1 binds to tau phosphorylated specifically on the Thr231–Pro site and probably catalyzes cis/ trans isomerization of pSer/Thr–Pro motif(s), thereby inducing conformational changes in tau. Such conformational changes can directly restore the ability of phosphorylated Tau to bind microtubules and promote microtubule assembly and/or facilitate tau dephosphorylation by its phosphatase PP2A, as PP2A activity is conformation-specific. Furthermore, Pin1 expression inversely correlates with the predicted neuronal vulnerability in normally aged brain and also with actual neurofibrillary degeneration in AD brain. Moreover, deletion of the gene encoding Pin1 in mice causes progressive age-dependent neuropathy characterized by motor and behavioral deficits, tau hyperphosphorylation, tau filament formation and neuronal degeneration. Distinct from all other mouse models where transgenic overexpression of specific proteins elicits tau-related pathologies, Pin1 is the first protein whose depletion causes age-dependent neurodegeneration and tau pathologies. Thus, Pin1 is pivotal in maintaining normal neuronal function and preventing age-dependent neurodegeneration. This could represent a promising interventive target to prevent neurodegenerative diseases.
Keywords: Alzheimer's disease; Pin1; Peptidyl-prolyl isomerase; Protein phosphorylation; Tau; Tauopathy
Tau and src family tyrosine kinases by Gloria Lee (pp. 323-330).
The interaction between tau and src family non-receptor tyrosine kinases represents a new function for tau. Mediated by the proline-rich region of tau and the SH3 domain of fyn or src, this interaction has the potential to confer novel cellular activities for tau in the growth cone and in the membrane. The subsequent finding that tau is tyrosine phosphorylated has led to the observation that tau in neurofibrillary tangles is tyrosine phosphorylated. Therefore, a role for tyrosine kinases such as fyn in neuropathogenesis is predicted.
Keywords: Tau; Src; Tyrosine kinase
Tau alteration and neuronal degeneration in tauopathies: mechanisms and models by Roland Brandt; Monika Hundelt; Neelam Shahani (pp. 331-354).
Tau becomes characteristically altered both functionally and structurally in several neurodegenerative diseases now collectively called tauopathies. Although increasing evidence supports that alterations of tau may directly cause neuronal degeneration and cell death, the mechanisms, which render tau to become a toxic agent are still unclear. In addition, it is obscure, whether neurodegeneration in tauopathies occurs via a common mechanism or specific differences exist. The aim of this review is to provide an overview about the different experimental models that currently exist, how they are used to determine the role of tau during degeneration and what has been learnt from them concerning the mechanistic role of tau in the disease process.The review begins with a discussion about similarities and differences in tau alteration in paradigmatic tauopathies such as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD).The second part concentrates on major experimental models that have been used to address the mechanistic role of tau during degeneration. This will include a discussion of cell-free assays, culture models using cell lines or dissociated neurons, and animal models. How these models aid to understand (i) alterations in the function of tau as a microtubule-associated protein (MAP), (ii) direct cytotoxicity of altered tau protein, and (iii) the potential role of tau aggregation in neurodegenerative processes will be the central theme of this part.The review ends with concluding remarks about a general mechanistic model of the role of tau alteration and neuronal degeneration in tauopathies and future perspectives.
Keywords: Abbreviations; AD; Alzheimer's disease; Aβ; amyloid β-protein; 3R; three-repeat tau; E; exon; 4R; four-repeat tau; FTDP-17; frontotemporal dementia and parkinsonism linked to chromosome 17; IR; inter-repeat; GSK-3β; glycogen synthase kinase-3β; MT; microtubule; MAP; microtubule-associated protein; NFTs; neurofibrillary tangles; NFL; neurofibrillary lesions; ND; not determined; PP2A; protein phosphatase 2A; PHF; paired helical filament; R; repeat; SF; straight filament; SP; senile plaquesAlzheimer's disease; Tau; Microtubule-associated protein; Neurofibrillary tangle; Paired helical filament; Neurodegeneration; Cytoskeleton; Tauopathy