An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline
Year: 2020
Type: article
Abstract: Tauopathies including Alzheimer's disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.
Source: Nature Communications
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,380
Funders: National Science Foundation, U.S. Department of Health and Human Services, Alzheimer's Association, American Federation for Aging Research, Association for Frontotemporal Degeneration, Michigan State University, CurePSP, Chan Zuckerberg Initiative, National Institutes of Health, College of Engineering, Michigan State University, Intellectual and Developmental Disabilities Research Center, National Institute on Aging, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1085565077, G1208415227, G1329876466, G1865494091, G2061063643, Clinical Translational Research Center for Neurodevelopmental Disorders, Dissecting the Role of HDAC6 in Alzheimer's Pathogenesis, G3602649364, North Carolina Translational & Clinical Sciences Institute (NC TraCS), G4340722137, Graduate research Fellowship Program (GRFP), UNC Neuroscience Center Research Cores, G4973067089, A pathogenic role for tau acetylation in Alzheimer's disease, G5931832048, G642530456, Identification of Endophenotypes in the Behavioral-Variant of Frontotemporal Deme, G744761297, G8028601682, G8343036966, G9000164381, G9000314134, Cancer Center Support Grant
OpenAlex ID: W3096112623