An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline

Hanna Trzeciakiewicz,Natallia V Riddick,Rebecca Lobrovich,Youjun Chen,Sheryl S Moy,Virginia M Y Lee,John Q Trojanowski,Aditi Ajit,Jui-Heng Tseng,Deepa Ajit,Ashutosh Tripathy,Zarin Tabassum,Michelle S Itano,Todd J Cohen,Claire Peterson,David J Irwin

doi:10.1038/s41467-020-19317-4

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.

Highlights

Tauopathies including Alzheimer’s disease (AD) are marked by the accumulation of aberrantly modified tau proteins
Neither polyubiquitin binding nor HDAC6 catalytic activity was required for HDAC6 binding to tau, removal of the Cterminal domain (1–840) or just deletion of the minimal SE14 domain (ΔSE14) significantly reduced tau binding without affecting total tau levels (Fig. 1b, c and Supplementary Fig. 1d)
Contrary to the notion that HDAC6 depletion alleviates neurodegeneration, our results suggest that HDAC6 acts in a protective capacity under conditions of tauopathy to suppress aberrant tau accumulation, and that sustained or chronic loss of HDAC6 results in accelerated tau pathology, cognitive dysfunction, and reduced survival

Summary

Introduction

Tauopathies including Alzheimer’s disease (AD) are marked by the accumulation of aberrantly modified tau proteins. The sheer abundance of tau acetylation within the MTBR (>25 lysine residues identified) and the ability of this modification to control tau binding to MTs, tau aggregation, and tau oligomer formation suggest that aberrant tau acetylation acts in a pathological manner to promote neurotoxicity and cognitive decline. HDAC6 inhibition or depletion could conceivably increase acetylated tau, promote tau aggregation, and lead to cognitive defects Consistent with this possibility, some studies have reported a neuroprotective role for HDAC6 in protein quality control (PQC)[20,21,22,23,24], including the ability to target misfolded proteins and damaged organelles for degradation[25,26]. We uncovered a novel mechanism through which HDAC6 suppresses aberrant tau accumulation, highlighting the loss of HDAC6 as a potential trigger for tau-mediated neurodegeneration

Methods

Results

Conclusion