Research ArticleParkinson’s Disease

A cullin-RING ubiquitin ligase targets exogenous α-synuclein and inhibits Lewy body–like pathology

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Science Translational Medicine  05 Jun 2019:
Vol. 11, Issue 495, eaau6722
DOI: 10.1126/scitranslmed.aau6722

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Promoting αSyn elimination

Lewy bodies (LBs) are protein aggregates found in the brain of patients with Parkinson’s disease (PD) that contribute to disease progression. α-Synuclein (αSyn) aggregates accumulate into LBs; however, the mechanisms mediating αSyn internalization and intracellular accumulation are not completely elucidated. Here, Gerez et al. showed that insoluble αSyn fibrils, but not monomers or small oligomers, were internalized and accumulated in neuronal cells. Upon internalization, a specific iron-regulated ubiquitin ligase mediated αSyn fibril degradation. Promoting this ubiquitinization counteracted LB formation and spreading in mouse models of αSyn accumulation. The results suggest that the ubiquitin complex described here might be a potential target for treating disorders associated with LB formation.