Membrane binding, internalization, and sorting of alpha-synuclein in the cell

Acta Neuropathologica Communications - Tập 6 - Trang 1-17 - 2018
Caterina Masaracchia1, Marilena Hnida1, Ellen Gerhardt1, Tomás Lopes da Fonseca1, Anna Villar-Pique1, Tiago Branco2, Markus A. Stahlberg3, Camin Dean3, Claudio O. Fernández4, Ira Milosevic2, Tiago F. Outeiro1,5,6
1Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Goettingen, Göttingen, Germany
2European Neuroscience Institute, University Medical Center Göttingen, Göttingen, Germany
3Trans-synaptic Signaling Group, European Neuroscience Institute, Goettingen, Germany
4Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario, Ocampo y Esmeralda, Rosario, Argentina
5Max-Planck-Institute for Experimental Medicine, Göttingen, Germany
6Institute of Neuroscience, The Medical School, Newcastle University, Newcastle Upon Tyne, UK

Tóm tắt

Alpha-synuclein (aSyn) plays a crucial role in Parkinson’s disease (PD) and other synucleinopathies, since it misfolds and accumulates in typical proteinaceous inclusions. While the function of aSyn is thought to be related to vesicle binding and trafficking, the precise molecular mechanisms linking aSyn with synucleinopathies are still obscure. aSyn can spread in a prion-like manner between interconnected neurons, contributing to the propagation of the pathology and to the progressive nature of synucleinopathies. Here, we investigated the interaction of aSyn with membranes and trafficking machinery pathways using cellular models of PD that are amenable to detailed molecular analyses. We found that different species of aSyn can enter cells and form high molecular weight species, and that membrane binding properties are important for the internalization of aSyn. Once internalized, aSyn accumulates in intracellular inclusions. Interestingly, we found that internalization is blocked in the presence of dynamin inhibitors (blocked membrane scission), suggesting the involvement of the endocytic pathway in the internalization of aSyn. By screening a pool of small Rab-GTPase proteins (Rabs) which regulate membrane trafficking, we found that internalized aSyn partially colocalized with Rab5A and Rab7. Initially, aSyn accumulated in Rab4A-labelled vesicles and, at later stages, it reached the autophagy-lysosomal pathway (ALP) where it gets degraded. In total, our study emphasizes the importance of membrane binding, not only as part of the normal function but also as an important step in the internalization and subsequent accumulation of aSyn. Importantly, we identified a fundamental role for Rab proteins in the modulation of aSyn processing, clearance and spreading, suggesting that targeting Rab proteins may hold important therapeutic value in PD and other synucleinopathies.

Tài liệu tham khảo

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