Tauopathy, including frontotemporal lobar dementia and Alzheimer’s disease, describes a class of neurodegenerative diseases characterized by the aberrant accumulation of Tau protein due to defects in proteostasis. Upon generating and characterizing a stable transgenic zebrafish that expresses the human TAU^P301L mutant in a neuron-specific manner, we found that accumulating Tau protein was efficiently cleared via an enhanced autophagy activity despite constant Tau mRNA expression; apparent tauopathy-like phenotypes were revealed only when the autophagy was genetically or chemically inhibited. We performed RNA-seq analysis, genetic knockdown, and rescue experiments with clinically relevant point mutations of valosin-containing protein (VCP), and showed that induced expression of VCP, an essential cytosolic chaperone for the protein quality system, was a key factor for Tau degradation via its facilitation of the autophagy flux. This novel function of VCP in Tau clearance was further confirmed in a tauopathy mouse model where VCP overexpression significantly decreased the level of phosphorylated and oligomeric/aggregate Tau and rescued Tau-induced cognitive behavioral phenotypes, which were reversed when the autophagy was blocked. Importantly, VCP expression in the brains of human Alzheimer’s disease patients was severely downregulated, consistent with its proposed role in Tau clearance. Taken together, these results suggest that enhancing the expression and activity of VCP in a spatiotemporal manner to facilitate the autophagy pathway is a potential therapeutic approach for treating tauopathy.

Tau蛋白病，包括额颞叶痴呆和阿尔茨海默氏病，描述了一类神经退行性疾病，其特征是由于蛋白质稳态缺陷导致Tau蛋白异常积累。在生成并表征以神经元特异性方式表达人类TAU ^P301L突变体的稳定转基因斑马鱼后，我们发现尽管 Tau mRNA 表达恒定，但通过增强的自噬活性可以有效清除累积的 Tau 蛋白；仅当自噬受到遗传或化学抑制时，才会出现明显的 tau 蛋白病样表型。我们对含缬洛辛蛋白 (VCP) 的临床相关点突变进行了 RNA-seq 分析、基因敲低和拯救实验，结果表明，VCP（蛋白质质量系统的重要胞质伴侣）的诱导表达是Tau 通过促进自噬通量而降解。 VCP 在 Tau 清除中的这一新功能在 tau 蛋白病小鼠模型中得到了进一步证实，其中VCP过表达显着降低了磷酸化和寡聚/聚集 Tau 的水平，并挽救了 Tau 诱导的认知行为表型，而当自噬被阻断时，这些认知行为表型会被逆转。重要的是，人类阿尔茨海默病患者大脑中的 VCP 表达严重下调，这与其在 Tau 清除中的作用一致。综上所述，这些结果表明，以时空方式增强 VCP 的表达和活性以促进自噬途径是治疗 tau 蛋白病的潜在治疗方法。