Gerez JA, Prymaczok NC, Rockenstein E, Herrmann US, Schwarz P, Adame A, Enchev RI, Courtheoux T, Boersema PJ, Riek R, Peter M, Aguzzi A, Masliah E, Picotti P

Parkinson's disease (PD) is a neurological disorder characterized by the progressive accumulation of neuronal ?-synuclein (?Syn) inclusions called Lewy bodies. It is believed that Lewy bodies spread throughout the nervous system due to the cell-to-cell propagation of ?Syn via cycles of secretion and uptake. Here, we investigated the internalization and ...

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intracellular accumulation of exogenous ?Syn, two key steps of Lewy body pathogenesis, amplification and spreading. We found that stable ?Syn fibrils substantially accumulate in different cell lines upon internalization, whereas ?Syn monomers, oligomers, and dissociable fibrils do not. Our data indicate that the uptake-mediated accumulation of ?Syn 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 ?Syn in cultured cells. Moreover, the SCF containing the F-box protein FBXL5 (SCFFBXL5) catalyzed ?Syn 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 ?Syn fibrils triggered a Lewy body-like pathology, which was amplified by SKP1 or FBXL5 loss of function. Our data thus indicate that SCFFXBL5 regulates ?Syn in vivo and that SCF ligases may constitute targets for the treatment of PD and other ?-synucleinopathies.

Date: Jun. 05, 2019

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