| First Author | Gerez JA | Year | 2019 |
| Journal | Sci Transl Med | Volume | 11 |
| Issue | 495 | PubMed ID | 31167929 |
| Mgi Jnum | J:275659 | Mgi Id | MGI:6313505 |
| Doi | 10.1126/scitranslmed.aau6722 | Citation | Gerez JA, et al. (2019) A cullin-RING ubiquitin ligase targets exogenous alpha-synuclein and inhibits Lewy body-like pathology. Sci Transl Med 11(495) |
| abstractText | Parkinson's disease (PD) is a neurological disorder characterized by the progressive accumulation of neuronal alpha-synuclein (alphaSyn) inclusions called Lewy bodies. It is believed that Lewy bodies spread throughout the nervous system due to the cell-to-cell propagation of alphaSyn via cycles of secretion and uptake. Here, we investigated the internalization and intracellular accumulation of exogenous alphaSyn, two key steps of Lewy body pathogenesis, amplification and spreading. We found that stable alphaSyn fibrils substantially accumulate in different cell lines upon internalization, whereas alphaSyn monomers, oligomers, and dissociable fibrils do not. Our data indicate that the uptake-mediated accumulation of alphaSyn 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 alphaSyn in cultured cells. Moreover, the SCF containing the F-box protein FBXL5 (SCF(FBXL5)) catalyzed alphaSyn 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 alphaSyn fibrils triggered a Lewy body-like pathology, which was amplified by SKP1 or FBXL5 loss of function. Our data thus indicate that SCF(FXBL5) regulates alphaSyn in vivo and that SCF ligases may constitute targets for the treatment of PD and other alpha-synucleinopathies. |
