Mitochondrial DNA polymorphisms as risk factors for Parkinson?s disease and Parkinson?s disease dementia

Abstract

The activity of complex I of the mitochondrial respiratory chain has been found to be decreased in patients with Parkinson's disease (PD), but no mutations have been identified in genes encoding complex I subunits. Recent studies have suggested that polymorphisms in mitochondrial DNA (mtDNA)-encoded complex I genes (MTND) modify susceptibility to PD. We hypothesize that the risk of PD is conveyed by the total number of nonsynonymous substitutions in the MTND genes in various mtDNA lineages rather than by single mutations. To test this possibility, we determined the number of nonsynonymous substitutions of the seven MTND genes from 183 Finns. The differences in the total number of nonsynonymous substitutions and the nonsynonymous to synonymous substitution rate ratio ( K(a)/ K(s)) of MTND genes between the European mtDNA haplogroup clusters (HV, JT, KU, IWX) were analysed by using a statistical approach. Patients with PD ( n=238) underwent clinical examination together with mtDNA haplogroup analysis and the clinical features between patient groups defined by the number of nonsynonymous substitutions were compared. Our analysis revealed that the haplogroup clusters HV and KU had a lower average number of amino acid replacements and a lower K(a)/ K(s) ratio in the MTND genes than clusters JT and IWX. Supercluster JTIWX with the highest number of amino acid replacements was more frequent among PD patients and even more frequent among patients with PD who developed dementia. Our results suggest that a relative excess of nonsynonymous mutations in MTND genes in supercluster JTWIX is associated with an increased risk of PD and the disease progression to dementia.

Mitochondria-Derived Damage-Associated Molecular Patterns in Neurodegeneration

“…Parkinson’s disease risk is associated with mtDNA haplotype, similar to AD (116–118). Changes to mtDNA are also observed in PD, such as mutations and deletions (119–121).…”

Shared Mechanisms of Neurodegeneration in Alzheimer’s Disease and Parkinson’s Disease

“…Studies have demonstrated that mitochondrial DNA was altered in some PD cases and that this alteration raised the risk of the disease by increasing ROS formation [49]. Deficiencies of mitochondrial complex I have been noted in brain and other tissues in postmortem PD studies [50].…”

Recent Advances in the Genetics of Parkinson's Disease

“…Defects in complex I activity are consistently observed in the substantia nigra of patients with PD (111) suggesting that mitochondrial dysfunction is central to PD pathogenesis. Over half of the proteins encoded by mitochondrial DNA assemble into complex I and certain mitochondrial DNA polymorphisms and haplotypes appear to reduce the risk for developing PD (5; 105), including a specific SNP that results in a threonine to alanine change in NADH3 of complex 1 which strongly associates with this protective effect (127). …”