Journal
HUMAN MOLECULAR GENETICS
Volume 21, Issue 15, Pages 3500-3512Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds161
Keywords
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Funding
- National Institutes of Health [R01 AG026938, RC1AG035610, P50 AG-16570, AG13854, R37 AG11762, P50-AG05142, P50 AG025688, R01 AG038791, R01 NS078086, R01 NS065782, P50 AG023501, P50NS072187]
- Tau Consortium
- Irene and Abe Pollin Fund for CBD Research
- CurePSP Foundation
- Peebler PSP Research Foundation
- NIHR Biomedical Research Centre for Mental Health at SLAM and KCL
- Medical Research Council
- Alzheimer's Research UK
- European Union [HEALTH-F4-2009-242257]
- Agence Nationale de la Recherche [R R08104DS]
- National Institute on Aging (NIA) [U24 AG21886, P30 AG19610]
- Arizona Department of Health Services [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation for Parkinson's Research
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Tau p.A152T significantly increases the risk for both FTD-s (n 2139, OR 3.0, CI: 1.65.6, P 0.0005) and Alzheimers disease (AD) (n 3345, OR 2.3, CI: 1.34.2, P 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.
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