Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases
Giovanni CoppolaSubashchandrabose ChinnathambiJason Ji Yong LeeBeth A. DombroskiMatt BakerAlexandra I. Soto‐OrtolazaSuzee E. LeeEric KleinAlden HuangRenee SearsJessica LaneAnna M. KarydasRobert O. KenetJacek BiernatLi San WangCarl W. CotmanCharles DeCarliAllan I. LeveyJohn M. RingmanMario F. MendezHelena C. ChuiIsabelle Le BerAlexis BriceMichelle K. LuptonElisavet PrezaSimon LovestoneJohn PowellNeill R. Graff‐RadfordRonald PetersenBradley F. BoeveCarol F. LippaEileen H. BigioIan R. MackenzieElizabeth FingerAndrew KerteszRichard J. CaselliMarla GearingJorge L. JuncosBernardino GhettiSalvatore SpinaYvette BordelonWallace W. TourtellotteMatthew P. FroschJean Paul VonsattelChris ZarowThomas G. BeachRoger L. AlbinAndrew P. LiebermanVirginia M. LeeJohn Q. TrojanowskiVivianna M. Van DeerlinThomas D. BirdDouglas GalaskoEliezer MasliahCharles L. WhiteJuan C. TroncosoDidier HannequinAdam L. BoxerMichael D. GeschwindSatish KumarEva‐Maria MandelkowZbigniew K. WszołekRyan J. UittiDennis W. DicksonJonathan L. HainesRichard MayeuxMargaret A. Pericak‐VanceLindsay A. FarrerLiana G. ApostolovaSteven E. ArnoldClinton T. BaldwinRobert C. BarberM. Michael BarmadaThomas G. BeachGary W. BeechamDuane BeeklyDavid A. BennettDeborah BlackerJames D. BowenAdam BoxerJames R. BurkeJacqueline L. BurosJoseph D. BuxbaumNigel J. CairnsLaura B. CantwellChuanhai CaoChris CarlsonRegina M. CarneyMinerva M. CarrasquilloSteven L. CarrollDavid G. ClarkJason J. CorneveauxPaul K. CraneCarlos CruchagaJeffrey L. CummingsPhilip L. De JagerCharles DeCarliSteven T. DeKoskyF. Yesim DemirciRamon Diaz‐ArrastiaMalcolm DickRanjan DuaraWilliam G. EllisNilüfer Ertekin‐TanerDenis EvansKelley M. FaberKenneth B. FallonMartin R. FarlowSteven H. FerrisTatiana M. ForoudPaul J. GallinsMary GanguliDaniel H. GeschwindJohn R. GilbertSid GilmanBruno GiordaniJonathan D. GlassAlison GoateNeill R. Graff‐RadfordRobert C. GreenJohn H. GrowdonHakon HakonarsonRonald L. HamiltonJohn HardyLindy E. HarrellElizabeth HeadLawrence S. HonigMatthew J. HuentelmanChristine M. HuletteBradley T. HymanGail P. JarvikGregory A. JichaLee Way JinNancy JohnsonGyungah JunM. Ilyas KambohJason KarlawishAnna KarydasJohn S. K. KauweJeffrey KayeRonald KimEdward H. KooNeil W. KowallPatricia KramerWalter A. KukullJames J. LahEric B. LarsonLorna M. LopezKathryn L. LunettaWendy J. MackDaniel MarsonEden R. MartinFrank MartiniukDeborah C. MashWayne C. McCormickSusan M. McCurryAndrew McDavidAnn C. McKeeMarsel MesulamBruce L. MillerCarol A. MillerJoshua W. MillerThomas J. MontineJohn C. MorrisAmanda MyersAdam C. NajPetra NowotnyJoseph E. ParisiDaniel P. PerlElaine R. PeskindWayne W. PoonHuntington PotterJoseph F. QuinnAshok RajRuchita RajbhandaryMurray A. RaskindEric M. ReimanBarry ReisbergChristiane ReitzErik D. RobersonEkaterina RogaevaRoger N. RosenbergMary SanoAndrew J. SaykinJulie A. SchneiderLon S. SchneiderWilliam W. SeeleyMichael L. ShelanskiMichael A. SliferCharles D. SmithJoshua A. SonnenPeter St George‐HyslopRobert A. SternRudolph E. TanziDebby W. TsuangBadri N. VardarajanHarry V. VintersJean Paul VonsattelSandra WeıntraubKathleen A. Welsh‐BohmerJennifer WilliamsonRandall L. WoltjerSteven G. YounkinOwen A. RossRosa RademakersDaniela BergEckhard Mandelkow
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Abstract:
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease.We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.Tau p.A152T significantly increases the risk for both FTD-s (n 5 2139, OR 5 3.0, CI: 1.6 -5.6, P 5 0.0005) and Alzheimer's disease (AD) (n 5 3345, OR 5 2.3, CI: 1.3 -4.2, P 5 0.004) compared with 9047 controls.Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers.However, there is a pronounced increase in the formation of tau oligomers.Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation.These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.Keywords:
Corticobasal degeneration
Tau protein
Neurodegenerative disorders referred to as tauopathies have cellular hyperphosphorylated tau protein aggregates in the absence of amyloid deposits. Comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. The six tau isoforms found in human brain contain either three (3R) or four microtubule-binding domains (4R). In Alzheimer's disease, all six tau isoforms are abnormally phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau55, 64 and 69). In corticobasal degeneration and progressive supranuclear palsy, only 4R-tau isoforms aggregate into twisted and straight filaments respectively. They appear as a major tau doublet (tau64 and 69). Finally, in Pick's disease, only 3R-tau isoforms aggregate into random coiled filaments. They are characterized by another major tau doublet (tau55 and 64). These differences in tau isoforms may be related to either the degeneration of particular cell populations in a given disorder or aberrant cell trafficking of particular tau isoforms. Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in fronto-temporal dementia with Parkinsonism linked to chromosome 17, demonstrating that tau aggregation is sufficient for nerve cell degeneration. Thus, tau mutations and polymorphisms may also be instrumental in many neurodegenerative disorders.
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Tau protein is the major component of the intracellular filamentous deposits that define a number of neurodegenerative diseases. They include the largely sporadic Alzheimers disease, progressive supranuclear palsy, corticobasal degeneration, Picks disease and argyrophilic grain disease, as well as the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Until recently, it was unclear whether the dysfunction of tau protein follows disease or whether disease follows the dysfunction of tau protein. The identification of mutations in Tau as the cause of FTDP-17 has resolved this issue by showing that the dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. 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. Surprisingly, the other mutations have their primary effect at the RNA level, thus perturbing the normal ratio of three-repeat to four-repeat tau isoforms. Where studied, this resulted in the relative overproduction of tau protein with four microtubule-binding repeats in brain. Several Tau mutations give rise to diseases that resemble progressive supranuclear palsy, corticobasal degeneration or Picks disease. Moreover, the H1 haplotype of Tau has been shown to be a significant risk factor for progressive supranuclear palsy and corticobasal degeneration. At an experimental level, the work on FTDP-17 is rapidly leading to the development of good transgenic mouse models for the human tauopathies. Keywords: Tauopathies, supranuclear, corticobasal, transgenic, FTDP-17
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Tau is the major component of the intracellular filamentous deposits that define a number of neurodegenerative diseases, including the largely sporadic Alzheimer's disease, 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 the dysfunction of tau protein. The identification of mutations in Tau as the cause of FTDP-17 has resolved this issue. About half of the known mutations have their primary effect at the protein level, and 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, thus perturbing the normal ratio of three-repeat to four-repeat tau isoforms. Where studied, this resulted in the relative overproduction of tau protein with four microtubule-binding repeats in brain. Several 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.
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The five studies forming this thesis deal with two closely related neurodegenerative diseases,progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), both of which are characterised by abundant tau-positive neuronal and glial filamentous inclusions and by
shared genetic risk factors[19, 70]. Four studies focus on demonstrating neuropathological, biochemical and genetic differences between the classical/typical form and atypical PSP while the fifth study discusses issues relevant for understanding disease progression in CBD.
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Coritcobasal degeneratin (CBD) has various neurological findings, such as cortical sign, parkinsonism, supranuclear palsy, myoclonus, and dementia. This disease used to be rare, but 20 years later, many case have been reported. Corticobasal degeneration is investigated from a wide range of specific analyses. It presents with a clinical resemblance to progressive supranuclear palsy (PSP) and it is important to determine whether CBD and PSP are the same entity. I will attempt to review the difference and similarities between PSP and CBD from a clinical standpoint.
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Tau, one of the major microtubule-associated proteins, modulates the dynamic properties of microtubules in the mammalian nervous system. Tau is abundantly expressed in the brain, particularly in the hippocampus. Insoluble and filamentous inclusions of tau in neurons or glia are discovered in neurodegenerative diseases termed ‘tauopathies’, including Alzheimer’s disease (AD), argyrophilic grain disease (AGD), corticobasal degeneration (CBD), frontotemporal dementia (FTD), Pick’s disease (PiD) and progressive supranuclear palsy (PSP). Accumulation of intracellular neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau, is directly correlated with the degree of Alzheimer\'s dementia. This chapter reviews the role of tau protein in physiological conditions and the pathological changes of tau related to neurodegenerative diseases. The applications of tau as a therapeutic target are also discussed.
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The clinical and neuropathological features characteristic of progressive supranuclear palsy and corticobasal degeneration are described in detail. These disorders are not as rare as previously believed, but are poorly recognized. In patients with parkinsonism, a high index of clinical suspicion, sometimes complemented by specific laboratory tests, should improve diagnostic accuracy. Biological treatments are at present not available, but suggested symptomatic therapies may improve the quality of life of patients with these disorders.
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Microtubule-associated protein tau encoded by the MAPT gene binds to microtubules and is important for maintaining neuronal morphology and function. Alternative splicing of MAPT pre-mRNA generates six major tau isoforms in the adult central nervous system resulting in tau proteins with three or four microtubule-binding repeat domains. In a group of neurodegenerative disorders called tauopathies, tau becomes aberrantly hyperphosphorylated and dissociates from microtubules, resulting in a progressive accumulation of intracellular tau aggregates. The spectrum of sporadic frontotemporal lobar degeneration associated with tau pathology includes progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. Alzheimer's disease is considered the most prevalent tauopathy. This review is divided into two broad sections. In the first section we discuss the molecular classification of sporadic tauopathies, with a focus on describing clinicopathologic relationships. In the second section we discuss the neuroimaging methodologies that are available for measuring tau pathology (directly using tau positron emission tomography ligands) and tau-mediated neuronal injury (magnetic resonance imaging and fluorodeoxyglucose positron emission tomography). Both sections have detailed descriptions of the following neurodegenerative dementias – Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease.
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