Journal
CELL REPORTS
Volume 35, Issue 4, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109037
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Funding
- National Institutes of Health (NIH) [R01AG061188, R21AG058080]
- Alzheimer's Association [NIRG-14-321219]
- Association for Frontotemporal Degeneration (AFTD) pilot grant
- American Federation for Aging Research (AFAR) [RAG15247]
- Cancer Center Core support grant [P30CA016086]
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The study found that P301L tau seeds are uniquely modified by post-translational modifications within the microtubule-binding region, which accelerates tau aggregation, enhances tau post-translational modification priming, and promotes prion-like templating. This complex post-translational regulation of transmissible tau seeds sheds light on the biological properties of tau strains in AD and other tauopathies.
The prion-like spread of tau pathology could underlie a spectrum of clinical syndromes including Alzheimer's disease (AD). Although evidence indicates that tau is transmissible, it is unclear how pathogenic tau seeds are processed in neurons. Here, we analyze fibrillar wild-type and disease-associated P301L tau seeds by using in vitro and neuronal assays. We show that P301L seeds are uniquely modified by post-translational modifications (PTMs) within the microtubule-binding region (MTBR). Although these modifications do not alter tau seed trafficking or localization, acetylated tau variants show accelerated tau aggregation, enhanced tau PTM priming, and prion-like templating. To explain the enhanced tau seed acetylation, we demonstrate that P301L seeds undergo auto-acetylation. Moreover, tau acts generally to inhibit HDAC6 deacetylase activity by preventing HDAC6 phosphorylation, leading to increased substrate acetylation. Our study highlights complex post-translational regulation of transmissible tau seeds and provides insight into the biological properties of tau strains in AD and other tauopathies.
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