UC San Diego

Autophagy (in the form of macroautophagy) is the major intracellular protein quality control system for removal of damaged organelles and abnormally aggregated proteins. We and others have shown that dysregulated autophagic pathways contribute to accumulation and spread of misfolded proteins in many neurodegenerative disorders, including Parkinson disease (PD) and Lewy body dementia (LBD). Additionally, generation of excessive reactive oxygen and nitrogen species, such as nitric oxide (NO), accelerates neuronal and synaptic damage mediated, at least in part, via aberrant protein S-nitrosylation. Using cell-based models, including human induced pluripotent stem cell (hiPSC)-derived neurons, CRISPR-Cas9 technology, and transgenic PD/LBD mice, plus vetting in human postmortem brains, we found that S-nitrosylation of the autophagic receptor protein SQSTM1/p62 (forming SNO-SQSTM1/p62) inhibits autophagic flux, thus contributing to accumulation of misfolded SNCA/α-synuclein. Consequently, this impairment in autophagy increases extracellular vesicle-dependent secretion and spread of aggregated SNCA. Taken together, our evidence suggests that aberrant formation of SNO-SQSTM1/p62 represents a pathogenic event contributing not only to inhibition of autophagic flux and potentiation of neuronal damage, but also to propagation of α-synucleinopathy between cells in the diseased brain.