Pathogenic mutations in Parkinson disease

Hum Mutat. 2007 Jul;28(7):641-53. doi: 10.1002/humu.20507.

Abstract

Parkinson disease (PD; Parkinson's) is the second most common neurodegenerative disease, characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies. Increasing evidence suggests that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system (UPS) dysfunction may represent the principal molecular pathways that commonly underlie the pathogenesis. The relative role of genetic and environmental factors has been the focus of research and debate. The recent discovery of a number of disease-causing genes (SNCA, Parkin/PARK2, UCHL1, PINK1, DJ1/PARK7, and LRRK2) in familial and sporadic forms of PD has provided considerable insights into the pathophysiology of this complex disorder. The frequency of these gene mutations may vary according to ethnicity and to the specific gene. A gene dosage effect is observed in some cases, and the phenotype of some of the mutation carriers closely resembles typical PD. Penetrance of some of the recurrent mutations is incomplete and may vary with age. Further research to unravel the etiopathology could identify biochemical or genetic markers for potential neuroprotective trials.

Publication types

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

MeSH terms

  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mutation*
  • Oncogene Proteins / genetics
  • Parkinson Disease / ethnology
  • Parkinson Disease / genetics*
  • Protein Deglycase DJ-1
  • Protein Kinases / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin-Protein Ligases / genetics
  • alpha-Synuclein / genetics

Substances

  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins
  • alpha-Synuclein
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • PTEN-induced putative kinase
  • Protein-Serine-Threonine Kinases
  • PARK7 protein, human
  • Protein Deglycase DJ-1
  • Ubiquitin Thiolesterase