A variant of the autophagic receptor NDP52 counteracts phospho-TAU accumulation and emerges as a protective factor for Alzheimer Disease

Abstract

ABSTRACTSelective elimination of early pathological TAU species may be a promising therapeutic strategy to reduce TAU accumulation that contributes to neurodegeneration and hallmarks Alzheimer disease (AD). By performing a genetic analysis of a cohort of 435 patients with AD, we defined the NDP52GEvariant (rs550510) of the autophagic receptor NDP52 (also known as CALCOCO2) as a protective factor for AD. We provide evidence that inin vitrosystems and in aDrosophila melanogastermodel of TAU-induced AD, NDP52 reduces the accumulation of pathological forms of TAU through the autophagic process and rescues typical neurodegenerative phenotypes induced by hTAU-toxicity. More importantly, we showed that the NDP52GEvariant is much more effective in this respect than NDP52WT. Mechanistically, we showed that NDP52 directly binds pathological phospho-TAU, and that NDP52WTand NDP52GEbind them with comparable efficiency. On the contrary, we showed that NDP52GEbinds the autophagic machinery (LC3C and LC3B) more efficiently than NDP52WT. We also showed for the first time that NDP52 is a direct target of protein phosphatase 2A (PP2A)in vitro, opening the way to the possibility that this phosphatase may fine-tune the autophagic function of NDP52 in AD. Finally, we found a positive correlation between the worldwide distribution of the allele encoding NDP52GEand the incidence or prevalence of AD. Overall, our work highlights the variant NDP52GEas a resilience factor in AD that shows a robust effectiveness to drive pathological TAU degradation.