1. |
|
|
2. |
|
|
3. |
- Burmann, Björn Marcus, 1979, et al.
(författare)
-
Regulation of alpha-synuclein by chaperones in mammalian cells
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 577:7788, s. 127-32
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
4. |
|
|
5. |
|
|
6. |
|
|