Regional expression of genes mediating trans-synaptic alpha-synuclein transfer predicts regional atrophy in Parkinson disease

Neuroimage Clin. 2018 Jan 31;18:456-466. doi: 10.1016/j.nicl.2018.01.009. eCollection 2018.

Abstract

Multiple genes have been implicated in Parkinson disease pathogenesis, but the relationship between regional expression of these genes and regional dysfunction across the brain is unknown. We address this question by joint analysis of high resolution magnetic resonance imaging data from the Parkinson's Progression Markers Initiative and regional genetic microarray expression data from the Allen Brain Atlas. Regional brain atrophy and genetic expression was co-registered to a common 86 region brain atlas and robust multivariable regression analysis was performed to identify genetic predictors of regional brain atrophy. Top candidate genes from GWAS analysis, as well as genes implicated in trans-synaptic alpha-synuclein transfer and autosomal recessive PD were included in our analysis. We identify three genes with expression patterns that are highly significant predictors of regional brain atrophy. The two most significant predictors are LAG3 and RAB5A, genes implicated in trans-synaptic synuclein transfer. Other well-validated PD-related genes do not have expression patterns that predict regional atrophy, suggesting that they may serve other roles such as disease initiation factors.

Keywords: Alpha-synuclein; Atrophy; Genetic analysis; LAG3; Parkinson disease; Trans-synaptic spread.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, CD / metabolism
  • Atrophy / etiology
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Brain / pathology*
  • Brain Mapping
  • Correlation of Data
  • Disease Progression
  • Female
  • Gene Expression Regulation / genetics*
  • Genetic Testing
  • Humans
  • Image Processing, Computer-Assisted
  • Magnetic Resonance Imaging
  • Male
  • Parkinson Disease / complications
  • Parkinson Disease / diagnostic imaging
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • alpha-Synuclein / metabolism*
  • rab5 GTP-Binding Proteins / metabolism

Substances

  • Antigens, CD
  • CD223 antigen
  • alpha-Synuclein
  • rab5 GTP-Binding Proteins