Department of Pharmacology, School of Basic Medical Science, Fudan University, Shanghai, China.
Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America.
PLoS Genet. 2021 Mar 17;17(3):e1009415. doi: 10.1371/journal.pgen.1009415. eCollection 2021 Mar.
Neurodegenerative diseases are characterized by neuron loss and accumulation of undegraded protein aggregates. These phenotypes are partially due to defective protein degradation in neuronal cells. Autophagic clearance of aggregated proteins is critical to protein quality control, but the underlying mechanisms are still poorly understood. Here we report the essential role of WDR81 in autophagic clearance of protein aggregates in models of Huntington's disease (HD), Parkinson's disease (PD) and Alzheimer's disease (AD). In hippocampus and cortex of patients with HD, PD and AD, protein level of endogenous WDR81 is decreased but autophagic receptor p62 accumulates significantly. WDR81 facilitates the recruitment of autophagic proteins onto Htt polyQ aggregates and promotes autophagic clearance of Htt polyQ subsequently. The BEACH and MFS domains of WDR81 are sufficient for its recruitment onto Htt polyQ aggregates, and its WD40 repeats are essential for WDR81 interaction with covalent bound ATG5-ATG12. Reduction of WDR81 impairs the viability of mouse primary neurons, while overexpression of WDR81 restores the viability of fibroblasts from HD patients. Notably, in Caenorhabditis elegans, deletion of the WDR81 homolog (SORF-2) causes accumulation of p62 bodies and exacerbates neuron loss induced by overexpressed α-synuclein. As expected, overexpression of SORF-2 or human WDR81 restores neuron viability in worms. These results demonstrate that WDR81 has crucial evolutionarily conserved roles in autophagic clearance of protein aggregates and maintenance of cell viability under pathological conditions, and its reduction provides mechanistic insights into the pathogenesis of HD, PD, AD and brain disorders related to WDR81 mutations.
神经退行性疾病的特征是神经元丧失和未降解的蛋白聚集体积累。这些表型部分归因于神经元细胞中蛋白降解的缺陷。聚集蛋白的自噬清除对于蛋白质质量控制至关重要，但潜在的机制仍知之甚少。在这里，我们报告了 WDR81 在亨廷顿病（HD）、帕金森病（PD）和阿尔茨海默病（AD）模型中对蛋白聚集体的自噬清除中的重要作用。在 HD、PD 和 AD 患者的海马体和皮质中，内源性 WDR81 的蛋白水平降低，但自噬受体 p62 显著积累。WDR81 促进自噬蛋白募集到 Htt 多聚 Q 聚集体上，并促进随后 Htt 多聚 Q 的自噬清除。WDR81 的 BEACH 和 MFS 结构域足以使其募集到 Htt 多聚 Q 聚集体上，其 WD40 重复序列对于 WDR81 与共价结合的 ATG5-ATG12 的相互作用是必需的。WDR81 的减少会损害小鼠原代神经元的活力，而过表达 WDR81 则恢复了 HD 患者成纤维细胞的活力。值得注意的是，在秀丽隐杆线虫中，WDR81 同源物（SORF-2）的缺失导致 p62 体的积累，并加剧了过表达的α-突触核蛋白诱导的神经元丧失。不出所料，SORF-2 或人 WDR81 的过表达恢复了线虫中的神经元活力。这些结果表明，WDR81 在蛋白聚集体的自噬清除和病理条件下细胞活力的维持中具有重要的进化保守作用，其减少为 HD、PD、AD 和与 WDR81 突变相关的脑疾病的发病机制提供了机制上的见解。
