Mattioni, A., Carsetti, C., Bruqi, K., Caputo, V., Cianfanelli, V., Bacalini, M.G., Casa, M., Gabelli, C., Giardina, E., Cestra, G., Strappazzon, F. (2025). A variant of the autophagic receptor NDP52 counteracts phospho-TAU accumulation and emerges as a protective factor for Alzheimer's disease.  Cell Death Dis. 16(1): 300.

FBrf0262083

Research paper

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.

PMC12000434 (PMC) (EuropePMC)