Related Experiment Videos
Mitochondrial DNA mutations in complex I and tRNA genes in Parkinson's disease
D K Simon1, R Mayeux, K Marder
1Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. dsimon1@caregroup.harvard.edu
Objective:
To identify mitochondrial DNA (mtDNA) mutations that predispose to PD.
Background:
Mitochondrial complex I activity is deficient in PD. mtDNA mutations may account for the defect, but the specific mutations have not been identified.
Methods:
Complete sequencing was performed of all mtDNA-encoded complex I and transfer RNA (tRNA) genes in 28 PD patients and 8 control subjects, as well as screening of up to 243 additional PD patients and up to 209 control subjects by restriction digests for selected mutations.
Results:
In the PD patients, 15 complex I missense mutations and 9 tRNA mutations were identified. After screening additional subjects, rare PD patients were found to carry complex I mutations that altered highly conserved amino acids. However, no significant differences were found in the frequencies of any mutations in PD versus control groups. The authors were unable to confirm previously reported associations of mutations at nucleotide positions (np) 4336, 5460, and 15927/8 with PD. Complex I mutations previously linked to Leber's hereditary optic neuropathy, one of which has been linked to atypical parkinsonism, were not associated with PD.
Conclusions:
mtDNA mutations with a high mutational burden (present in a high percentage of mtDNA molecules in an individual) in complex I or tRNA genes do not play a major role in the risk of PD in most PD patients. Further investigations are necessary to determine if any of the rare mtDNA mutations identified in PD patients play a role in the pathogenesis of PD in those few cases.
Insights
Mitochondrial DNA (mtDNA) mutations in complex I or tRNA genes do not significantly increase Parkinson
Area of Science:
- Neurogenetics
- Mitochondrial Biology
- Parkinson's Disease Research
Background:
- Parkinson's disease (PD) is associated with deficient mitochondrial complex I activity.
- Mitochondrial DNA (mtDNA) mutations are hypothesized to cause this complex I defect in PD.
- Specific causative mtDNA mutations in PD remain unidentified.
Purpose of the Study:
- To identify specific mitochondrial DNA (mtDNA) mutations that may predispose individuals to Parkinson's disease (PD).
- To investigate the role of complex I and tRNA gene mutations in PD pathogenesis.
Main Methods:
- Complete sequencing of all mtDNA-encoded complex I and tRNA genes in PD patients and controls.
- Screening of additional PD patients and controls for selected mtDNA mutations using restriction digests.
Main Results:
- Identified 15 complex I missense and 9 tRNA mutations in PD patients.
- Rare PD patients carried complex I mutations affecting highly conserved amino acids.
- No significant differences in mutation frequencies were observed between PD and control groups.
- Previously reported PD-associated mutations and those linked to Leber's hereditary optic neuropathy were not associated with PD in this study.
Conclusions:
- High-burden mtDNA mutations in complex I or tRNA genes are unlikely to be a major risk factor for PD in the majority of patients.
- Further research is needed to explore the potential role of rare mtDNA mutations in the pathogenesis of PD in a subset of individuals.