Gene-environment interactions in Parkinson's disease and other forms of parkinsonism.
It is widely recognized that both genetic and environmental factors are likely to contribute to the pathogenesis of human parkinsonism. While the identification of specific predisposing conditions and mechanisms of disease development remain elusive, new discoveries coupled with technological advances over the past decade have provided important clues. From the genetic standpoint, both causal and susceptibility genes have been identified, with some of these genes pointing to gene-environment interactions. The application of emerging genomic technologies, such as Genome Wide Association Studies (GWAS), will certainly further our knowledge of Parkinson's disease (PD)-related genes. From the environmental perspective, toxicant-induced models of parkinsonian syndromes, such as those associated with exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or beta-N-methylamino-l-alanine (BMAA), have revealed potential mechanisms of increased susceptibility based on genetic predisposition. Finally, new hypotheses on mechanisms of disease development include the possibility that exposure to neurotoxicants triggers an upregulation and pathological modifications of alpha-synuclein. Mutations in the alpha-synuclein gene are responsible for rare familial cases of parkinsonism, and polymorphisms in the promoter region of this gene confer a higher susceptibility to idiopathic PD. Thus, toxicant-alpha-synuclein interactions could have deleterious consequences and play a role in pathogenetic processes in human parkinsonism.
Vance
Jeffery M
JM
University of Miami, Miami, FL 33101, USA.
Ali
Syed
S
Bradley
Walter G
WG
Singer
Carlos
C
Di Monte
Donato A
DA
D000818:Animals; D004195:Disease Models, Animal; D004777:Environment; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000150:complications / Q000235:genetics
D009419:Nerve Tissue Proteins; D009498:Neurotoxins