Neurodegenerative aspects of multiple system atrophy

Rowan Radford, Mathew Wong, Dean L. Pountney*

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

10 Citations (Scopus)

Abstract

Multiple system atrophy (MSA) closely resembles Parkinson's disease clinically but with a range of autonomic signs in addition to motor symptoms, resulting in its designation as a Parkinson's-plus disease/atypical parkinsonism. However, unlike Parkinson's disease that displays primarily neuronal pathology, the neurodegenerative aspects of MSA reflect widespread glial cell dysfunction and the occurrence of intracytoplasmic inclusion bodies predominantly in oligodendrocytes. Alpha-synuclein, a key protein component of the glial cytoplasmic inclusions, is thought to mediate cytotoxicity via a range of abnormal modified and aggregated soluble molecular species that may even propagate from cell to cell as cargo in exosomes. Moreover, cellular model studies suggest that the sequestration of abnormal alpha-synuclein within microscopically visible intracellular inclusion bodies occurs as a defensive response that utilizes the aggresome machinery. Although aggregation of alpha-synuclein plays a central role in the disease pathology, it is becoming clear that there is a complex interplay of factors, including heat shock proteins, inflammation, calcium homeostasis, the ubiquitin proteasome system, autophagy, and oxidative stress. Recent studies have highlighted the involvement of metallothioneins, small ubiquitin-like modifier (SUMO), and p25a, thus providing several new potential targets for therapeutic intervention. Inflammatory pathways may also be exploited in new treatment approaches, although it remains to be determined whether the astrocyte and microglial activation present is secondary to alpha-synuclein aggregation or primary to the disease pathogenesis, and may even have some beneficial consequences.

Original languageEnglish
Title of host publicationHandbook of neurotoxicity
EditorsRichard M. Kostrzewa
Place of PublicationNew York
PublisherSpringer, Springer Nature
Pages2157-2180
Number of pages24
Volume3
ISBN (Electronic)9781461458364
ISBN (Print)9781461458357
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

Keywords

  • Aggresome
  • Alpha-synuclein
  • Autophagy
  • Calcium
  • Chaperones
  • Metallothionein
  • Multiple system atrophy
  • Neuroinflammation
  • SUMO

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