Reduction of WDR81 impairs autophagic clearance of aggregated proteins and cell viability in neurodegenerative phenotypes

• DOI: 10.1371/journal.pgen.1009415
• Publication Date: 2021-03-17T17:39:25Z
• Authors: Xuezhao Liu; Limin Yin; Tianyou Li; Lingxi Lin; Jie Zhang; Yang Li
• Keywords: Viability assay

Neurodegenerative diseases are characterized by neuron loss and accumulation of undegraded protein aggregates. These phenotypes partially due to defective degradation in neuronal cells. Autophagic clearance aggregated proteins is critical quality control, but the underlying mechanisms still poorly understood. Here we report essential role WDR81 autophagic aggregates models Huntington’s disease (HD), Parkinson’s (PD) Alzheimer’s (AD). In hippocampus cortex patients with HD, PD AD, level endogenous decreased receptor p62 accumulates significantly. facilitates recruitment onto Htt polyQ promotes subsequently. The BEACH MFS domains sufficient for its aggregates, WD40 repeats interaction covalent bound ATG5-ATG12. Reduction impairs viability mouse primary neurons, while overexpression restores fibroblasts from HD patients. Notably, Caenorhabditis elegans , deletion homolog (SORF-2) causes bodies exacerbates induced overexpressed α-synuclein. As expected, SORF-2 or human worms. results demonstrate that has crucial evolutionarily conserved roles maintenance cell under pathological conditions, reduction provides mechanistic insights into pathogenesis PD, AD brain disorders related mutations.