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Mitochondrial DNA mutations in complex I and tRNA genes in Parkinson’s disease

From the Departments of Neurology (Drs. Simon and Johns), and Ophthalmology (Dr. Johns), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Gertrude H. Sergievsky Center (Drs. Mayeux and Marder) and Departments of Neurology (Drs. Mayeux and Marder) and Psychiatry (Dr. Mayeux), College of Physicians and Surgeons, and Division of Epidemiology, School of Public Health (Dr. Mayeux), Columbia University, New York, NY; Geriatric Research Education and Clinical Center, Bedford VAMC (Dr. Kowall) and Department of Neurology, Boston University School of Medicine, Boston, MA; Department of Neurology and Neuroscience (Dr. Beal), Weill Medical College of Cornell University, New York, NY.

Address correspondence and reprint requests to Dr. D.K. Simon, Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, HIM 847, 77 Avenue Louis Pasteur, Boston, MA 02115; e-mail: dsimon1{at}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.

Key words: PD—Leber’s hereditary optic neuropathy—Mitochondrial DNA—NAD(P)H dehydrogenase (quinone)—Transfer RNA—Polymorphism

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