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Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Disentangling the Role of the Tau Gene Locus in Sporadic Tauopathies

Author(s): J. Vandrovcova, F. Anaya, V. Kay, A. Lees, J. Hardy and R. de Silva

Volume 7, Issue 8, 2010

Page: [726 - 734] Pages: 9

DOI: 10.2174/156720510793611619

Price: $65


Fibrillar aggregates of abnormally hyperphosphorylated tau protein are the major component of the pathological entities, including intraneuronal neurofibrillary tangles that define the broad class of late-onset neurodegenerative disorders called the tauopathies. Mutations in the tau gene (MAPT) causing familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) confirm that tau protein dysfunction could be a primary cause of neuronal loss. However, in the sporadic tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) where MAPT mutation is absent, common variation in MAPT that defines the H1 and H2 haplotype clades strongly influences disease risk. Surprisingly, this influence on risk extends to sporadic Parkinsons disease (PD), traditionally not defined as a tauopathy. This review will focus on recent work aimed at elucidating the mechanistic basis of this haplotypespecific effect on disease risk, implicating elevated levels of MAPT expression, particularly via increased transcription and/or alterations in splicing. This conforms to an emerging picture of a shared mechanism that underlies the fundamental process(es) leading to neuronal death. Increased availability of the fibrillogenic protein substrates of the pathological aggregates that define several neurodegenerative proteopathies, eg α-synuclein in PD, β-amyloid in AD and tau in the tauopathies, contributes to causation and risk in the familial and sporadic forms of these disorders, respectively.

Keywords: Tau, tauopathy, alzheimer, parkinsonism, genetics, progressive supranuclear palsy.

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