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Abundance of Synaptic Vesicle-Related Proteins in Alpha-Synuclein-Containing Protein Inclusions Suggests a Targeted Formation Mechanism

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Abstract

Proteinaceous α-synuclein-containing inclusions are found in affected brain regions in patients with Parkinson’s disease (PD), Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). These appear in neurons as Lewy bodies in both PD and DLB and as glial cytoplasmic inclusions (GCIs) in oligodendrocytes in MSA. The role they play in the pathology of the diseases is unknown, and relatively little is still known about their composition. By purifying the inclusions from the surrounding tissue and comprehensively analysing their protein composition, vital clues to the formation mechanism and role in the disease process may be found. In this study, Lewy bodies were purified from postmortem brain tissue from DLB cases (n = 2) and GCIs were purified from MSA cases (n = 5) using a recently improved purification method, and the purified inclusions were analysed by mass spectrometry. Twenty-one percent of the proteins found consistently in the GCIs and LBs were synaptic-vesicle related. Identified proteins included those associated with exosomes (CD9), clathrin-mediated endocytosis (clathrin, AP-2 complex, dynamin), retrograde transport (dynein, dynactin, spectrin) and synaptic vesicle fusion (synaptosomal-associated protein 25, vesicle-associated membrane protein 2, syntaxin-1). This suggests that the misfolded or excess α-synuclein may be targeted to inclusions via vesicle-mediated transport, which also explains the presence of the neuronal protein α-synuclein within GCIs.

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Acknowledgements

We would like to acknowledge Dr. Weiping Gai for the anti-α-synuclein antibody, Ms. Fariba Chegini for her assistance with immunofluoresence and the South Australian Brain Bank for their support.

Funding

This study is financially supported by the Flinders Medical Centre Research Foundation, South Australia.

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Authors and Affiliations

  1. Flinders Proteomics Facility, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, 5042, Australia

    Amellia McCormack, Nusha Chegeni, Alex Colella & Tim Chataway

  2. College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, 5042, Australia

    Damien J. Keating

  3. Department of Immunology, Flinders Medical Centre and Flinders University, SA Pathology, Bedford Park, South Australia, 5042, Australia

    Alex Colella & Jing Jing Wang

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  1. Amellia McCormack
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  2. Damien J. Keating
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Correspondence to Tim Chataway.

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McCormack, A., Keating, D.J., Chegeni, N. et al. Abundance of Synaptic Vesicle-Related Proteins in Alpha-Synuclein-Containing Protein Inclusions Suggests a Targeted Formation Mechanism. Neurotox Res 35, 883–897 (2019). https://doi.org/10.1007/s12640-019-00014-0

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  • DOI: https://doi.org/10.1007/s12640-019-00014-0

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