OPTN attenuates the neurotoxicity of abnormal Tau protein by restoring autophagy

OPTN is an autophagy receptor involved in autophagic degradation. Here we studied the role of OPTN in attenuating the neurotoxicity induced by mutated Tau protein. We constructed recombinant adeno-associated viruses with OPTN and Tau-P301L genes, respectively. Through virus coinfection on neuronal cell line HT22 in vitro and Kunming mice in vivo, we found that autophagy- and apoptosis-associated genes are altered by Tau-P301L at both mRNA and protein levels, which are restored by OPTN expression. Functionally, OPTN suppresses apoptosis and enhances cellular viability in Tau-P301L expressing HT22 cells, and increases learning and memory in Tau-P301L expressing mice, respectively. Last, we found that OPTN reduces the p-Tau levels in vitro and in vivo. Our results reveal the function of OPTN in lowering the p-Tau level and the expressions of apoptosis genes, and increasing the expressions of autophagic genes, indicating a beneficial role of OPTN in Tau pathology.