Histone deacetylase-6 ZnF UBP as a regulator of tau stability and neuronal functions

Abstract

Alzheimer`s disease (AD) is an age associated Neurodegenerative disease, which have two key players involved in its pathogenesis-Amyloid-β peptide and microtubule-associated protein Tau (MAPT). The aggregates consisting of these two are found in the brains of AD patient. Amyloid-β peptides form extracellular plaques while Tau forms intracellular neurofibrillary tangles (NFT). HDAC6 is a class II histone deacetylase majorly present in the cytoplasm. It plays an important role in aggresome formation by recruiting polyubiquitinated aggregates to the motor protein dynein. Here, we have studied the effect of HDAC6 ZnF UBP domain as a modifier of Tau aggregation by its direct interaction with the polyproline region/repeat region of Tau. Interaction of HDAC6 ZnF UBP with Tau was found to reduce the propensity of Tau to self-aggregate as well as to disaggregate pre-formed aggregates. Additionally, conformational changes in Tau protein and its accelerated degradation with HDAC6 ZnF UBP suggest a mechanism by which it either acts on Tau to degrade or enhance its auto-proteolysis. Immunocytochemistry revealed that HDAC6 ZnF UBP can modulate Tau phosphorylation and actin cytoskeleton organization when the cells are exposed to the domain. HDAC6 ZnF UBP treatment to cells resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia-like structures and podonuts suggesting its role in actin re-organization. Also, HDAC6 treatment showed increased nuclear localization of ApoE and tubulin localization in MTOC. All these findings suggest the regulatory role of this domain in different aspects apart from its well-known function in aggresome formation. We also explored the potency of two small molecules – Melatonin and Baicalein in the disaggregation of Tau aggregates. Both these molecules have a pleiotropic role with respect to neuronal health. In our studies, we found that both Melatonin and Baicalein can interact with Tau to bring about dissolution of Tau aggregates. We hypothesized for the mechanism of action of Melatonin and Baicalein and proposed these