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

Amellia McCormack, Damien J. Keating, Nusha Chegeni, Alex Colella, Jing Jing Wang, Tim Chataway

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)883-897
Number of pages15
JournalNeurotoxicity Research
Volume35
Issue number4
Early online date22 Feb 2019
DOIs
Publication statusPublished - 15 May 2019

Keywords

  • Lewy body
  • glial cytoplasmic inclusion
  • Parkinson's disease
  • multiple system atrophy
  • Glial cytoplasmic inclusion
  • Vesicle trafficking
  • Multiple system atrophy
  • Mass spectrometry
  • Parkinson’s disease

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