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

Selective elimination of early pathological TAU species may be a promising therapeutic strategy to reduce the accumulation of TAU, which contributes to neurodegeneration and is a hallmark of Alzheimer's disease (AD). Pathological hyper-phosphorylated TAU can be degraded through selective autophagy, and NDP52/CALCOCO2 is one of the autophagy receptors involved in this process. In 2021, we discovered a variant of NDP52, called NDP52^GE (rs550510), that is more efficient at promoting autophagy. We here anticipate that this variant could be a powerful factor that could eliminate pathological forms of TAU better than its WT form (NDP52^WT). Indeed, we provide evidence that in in vitro systems and in a Drosophila melanogaster model of TAU-induced AD, the NDP52^GE variant is much more effective than the NDP52^WT in reducing the accumulation of pathological forms of TAU through the autophagic process and rescues typical neurodegenerative phenotypes induced by hTAU toxicity. Mechanistically, we showed that NDP52^WT and NDP52^GE bind pTAU with comparable efficiency, but that NDP52^GE binds the autophagic machinery (LC3C and LC3B) more efficiently than NDP52^WT does, which could explain its greater efficiency in removing pTAU. Finally, by performing a genetic analysis of a cohort of 435 AD patients, we defined the NDP52^GE variant as a protective factor for AD. Overall, our work highlights the variant NDP52^GE as a resilience factor in AD that shows a robust effectiveness in driving pathological TAU degradation.