Abstract
Mutations in the gene encoding tau (MAPT) cause frontotemporal dementia spectrum disorders. A rare tau variant p.A152T was reported as a risk factor for frontotemporal dementia spectrum and Alzheimer's disease in an initial case-control study. Such findings need replication in an independent cohort. We analysed an independent multinational cohort comprising 3100 patients with neurodegenerative disease and 4351 healthy control subjects and found p.A152T associated with significantly higher risk for clinically defined frontotemporal dementia and progressive supranuclear palsy syndrome. To assess the functional and biochemical consequences of this variant, we generated transgenic zebrafish models expressing wild-type or A152T-tau, where A152T caused neurodegeneration and proteasome compromise. Impaired proteasome activity may also enhance accumulation of other proteins associated with this variant. We increased A152T clearance kinetics by both pharmacological and genetic upregulation of autophagy and ameliorated the disease pathology observed in A152T-tau fish. Thus, autophagy-upregulating therapies may be a strategy for the treatment for tauopathies.
Original language | English (US) |
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Pages (from-to) | 1128-1146 |
Number of pages | 19 |
Journal | Brain |
Volume | 140 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2017 |
Funding
Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank the Tau consortium (SEL, ALB, GC, BLM, DCR), P50 AG02350, P01 AG019724, R01AG038791, U54NS092089, F31 NS084556, Alzheimer’s Research UK (DCR) Wellcome Trust (Principal Research Fellowship to 095317/Z/11/Z), a Wellcome Trust Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/ Z), NIHR Biomedical Research Unit in Dementia at Addenbrooke’s Hospital, the John Douglas French Alzheimer’s Foundation for funding. L.S. is funded by a DFG fellowship, N.V.O. is funded by BBSRC project grant BB/L000830/1.
Keywords
- autophagy
- neurodegeneration
- proteasome
- tauopathy
ASJC Scopus subject areas
- Clinical Neurology