期刊
NATURE
卷 577, 期 7788, 页码 127-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-019-1808-9
关键词
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资金
- Swiss National Science Foundation [PP00P3_128419, PZ00P3_148238, PMPDP3_164425]
- European Research Council (FP7) [MOMP 281764]
- Swedish Research Council
- Knut and Alice Wallenberg Foundation through a Wallenberg Academy Fellowship
- Knut and Alice Wallenberg Foundation through a Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden
- ZonMW TOP grant [91215084]
- Marie-Curie Actions of the 7th Framework programme of the EU [608180]
- Swiss National Science Foundation (SNF) [PZ00P3_148238, PMPDP3_164425] Funding Source: Swiss National Science Foundation (SNF)
Neurodegeneration in patients with Parkinson's disease is correlated with the occurrence of Lewy bodies-intracellular inclusions that contain aggregates of the intrinsically disordered protein alpha-synuclein(1). The aggregation propensity of alpha-synuclein in cells is modulated by specific factors that include post-translational modifications(2,3), Abelson-kinase-mediated phosphorylation(4,5) and interactions with intracellular machineries such as molecular chaperones, although the underlying mechanisms are unclear(6-8). Here we systematically characterize the interaction of molecular chaperones with alpha-synuclein in vitro as well as in cells at the atomic level. We find that six highly divergent molecular chaperones commonly recognize a canonical motif in alpha-synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of alpha-synuclein. NMR experiments(9) in cells show that the same transient interaction pattern is preserved inside living mammalian cells. Specific inhibition of the interactions between alpha-synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90 beta, results in transient membrane binding and triggers a remarkable re-localization of alpha-synuclein to the mitochondria and concomitant formation of aggregates. Phosphorylation of alpha-synuclein at Tyr39 directly impairs the interaction of alpha-synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase in Parkinson's disease. Our results establish a master regulatory mechanism of alpha-synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and highlighting new perspectives for therapeutic interventions for Parkinson's disease.
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