Header

UZH-Logo

Maintenance Infos

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


Gerez, Juan A; Prymaczok, Natalia C; Rockenstein, Edward; Herrmann, Uli S; Schwarz, Petra; Adame, Anthony; Enchev, Radoslav I; Courtheoux, Thibault; Boersema, Paul J; Riek, Roland; Peter, Matthias; Aguzzi, Adriano; Masliah, Eliezer; Picotti, Paola (2019). A cullin-RING ubiquitin ligase targets exogenous α-synuclein and inhibits Lewy body–like pathology. Science Translational Medicine, 11(495):eaau6722.

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 (SCF<jats:sup>FBXL5</jats:sup>) 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 SCF<jats:sup>FXBL5</jats:sup> regulates αSyn in vivo and that SCF ligases may constitute targets for the treatment of PD and other α-synucleinopathies.

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 (SCF<jats:sup>FBXL5</jats:sup>) 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 SCF<jats:sup>FXBL5</jats:sup> regulates αSyn in vivo and that SCF ligases may constitute targets for the treatment of PD and other α-synucleinopathies.

Statistics

Citations

Dimensions.ai Metrics

Altmetrics

Downloads

2 downloads since deposited on 15 Aug 2019
2 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:General Medicine
Language:English
Date:5 June 2019
Deposited On:15 Aug 2019 14:02
Last Modified:13 Oct 2019 05:57
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
OA Status:Closed
Publisher DOI:https://doi.org/10.1126/scitranslmed.aau6722
Project Information:
  • : FunderFP7
  • : Grant ID277147
  • : Project TitleFOLDTOX - Understanding the cytotoxicity of aberrantly folded proteins in neurodegeneration
  • : FunderFP7
  • : Grant ID337603
  • : Project TitleQMULT - Multipartite Quantum Information Theory
  • : FunderFP7
  • : Grant ID277147
  • : Project TitleFOLDTOX - Understanding the cytotoxicity of aberrantly folded proteins in neurodegeneration
  • : FunderFP7
  • : Grant ID337603
  • : Project TitleQMULT - Multipartite Quantum Information Theory
  • : FunderSNSF
  • : Grant IDPP00P3_133670
  • : Project TitleUnderstanding the mechanisms of cytotoxic response to aberrantly-folded and aggregated proteins

Download