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.

Abstract

Parkinson’s disease (PD) is a neurological disorder characterized by the progressive accumulation of neuronal α-synuclein (αSyn) inclusions called Lewy bodies. It is believed that Lewy bodies spread throughout the nervous system due to the cell-to-cell propagation of αSyn via cycles of secretion and uptake. Here, we investigated the internalization and intracellular accumulation of exogenous αSyn, two key steps of Lewy body pathogenesis, amplification and spreading. We found that stable αSyn fibrils substantially accumulate in different cell lines upon internalization, whereas αSyn monomers, oligomers, and dissociable fibrils do not. Our data indicate that the uptake-mediated accumulation of αSyn in a human-derived neuroblastoma cell line triggered an adaptive response that involved proteins linked to ubiquitin ligases of the S-phase kinase-associated protein 1 (SKP1), cullin-1 (Cul1), and F-box domain–containing protein (SCF) family. We found that SKP1, Cul1, and the F-box/LRR repeat protein 5 (FBXL5) colocalized and physically interacted with internalized αSyn in cultured cells. Moreover, the SCF containing the F-box protein FBXL5 (SCFFBXL5) catalyzed αSyn ubiquitination in reconstitution experiments in vitro using recombinant proteins and in cultured cells. In the human brain, SKP1 and Cul1 were recruited into Lewy bodies from brainstem and neocortex of patients with PD and related neurological disorders. In both transgenic and nontransgenic mice, intracerebral administration of exogenous αSyn fibrils triggered a Lewy body–like pathology, which was amplified by SKP1 or FBXL5 loss of function. Our data thus indicate that SCFFXBL5 regulates αSyn in vivo and that SCF ligases may constitute targets for the treatment of PD and other α-synucleinopathies.

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