Cross-examining candidate genes implicated in multiple system atrophy

Acta Neuropathol Commun. 2019 Jul 24;7(1):117. doi: 10.1186/s40478-019-0769-4.


Multiple system atrophy (MSA) is a devastating neurodegenerative disease characterized by the clinical triad of parkinsonism, cerebellar ataxia and autonomic failure, impacting on striatonigral, olivopontocerebellar and autonomic systems. At early stage of the disease, the clinical symptoms of MSA can overlap with those of Parkinson's disease (PD). The key pathological hallmark of MSA is the presence of glial cytoplasmic inclusions (GCI) in oligodendrocytes. GCI comprise insoluble proteinaceous filaments composed chiefly of α-synuclein aggregates, and therefore MSA is regarded as an α-synucleinopathy along with PD and dementia with Lewy bodies. The etiology of MSA is unknown, and the pathogenesis of MSA is still largely speculative. Much data suggests that MSA is a sporadic disease, although some emerging evidence suggests rare genetic variants increase susceptibility. Currently, there is no general consensus on the susceptibility genes as there have been differences due to geographical distribution or ethnicity. Furthermore, many of the reported studies have been conducted on patients that were only clinically diagnosed without pathological verification. The purpose of this review is to bring together available evidence to cross-examine the susceptibility genes and genetic pathomechanisms implicated in MSA. We explore the possible involvement of the SNCA, COQ2, MAPT, GBA1, LRRK2 and C9orf72 genes in MSA pathogenesis, highlight the under-explored areas of MSA genetics, and discuss future directions of research in MSA.

Keywords: COQ2; GWAS; Multiple system atrophy; Parkinson’s disease; Susceptibility genes; α-Synuclein.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alkyl and Aryl Transferases / genetics
  • Brain / pathology*
  • C9orf72 Protein / genetics
  • Genetic Predisposition to Disease
  • Glucosylceramidase / genetics
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Multiple System Atrophy / genetics*
  • Multiple System Atrophy / pathology*
  • Neurons / pathology
  • alpha-Synuclein / genetics
  • tau Proteins / genetics


  • C9orf72 Protein
  • C9orf72 protein, human
  • MAPT protein, human
  • SNCA protein, human
  • alpha-Synuclein
  • tau Proteins
  • Alkyl and Aryl Transferases
  • 4-hydroxybenzoate polyprenyltransferase
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • GBA protein, human
  • Glucosylceramidase