title: Somatic mitochondrial DNA mutations do not increase neuronal  vulnerability to MPTP in young POLG mutator mice.
abstract: Mitochondrial DNA (mtDNA) mutations are hypothesized to play a pathogenic role in aging and age-related neurodegenerative diseases such as Parkinson's disease (PD). In support of this, high levels of somatic mtDNA mutations in “POLG mutator” mice carrying a proofreading-deficient form of mtDNA polymerase ã (Polg(D257A)) lead to a premature aging phenotype. However, the relevance of this finding to the normal aging process has been questioned as the number of mutations is greater even in young POLG mutator mice, which shows no overt phenotype, than levels achieved during normal aging in mice. Vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) increases with age, and we hypothesized that this may result in part from the accumulation with age of somatic mtDNA mutations. If correct, then levels of mutations in young (2–3 month old) POLG mutator mice should be sufficient to increase vulnerability to MPTP. In contrast, we find that susceptibility to MPTP in both heterozygous and homozygous POLG mutator mice at this young age is not different from that of wild type littermate controls as measured by levels of tyrosine hydroxylase positive (TH+) striatal terminals, striatal dopamine and its metabolites, a marker of oxidative damage, or stereological counts of TH+ and total substantia nigra neurons. These unexpected results do not support the hypothesis that somatic mtDNA mutations contribute to the age-related vulnerability of dopaminergic neurons to MPTP. It remains possible that somatic mtDNA mutations influence vulnerability to other stressors, or require additional time for the deleterious consequences to manifest. Furthermore, the impact of the higher levels of mutations present at older ages in these mice was not assessed in our study, although a prior study also failed to detect an increase in vulnerability to MPTP in older mice. With these caveats, the current data do not provide evidence for a role of somatic mtDNA mutations in determining the vulnerability to MPTP.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. ydai@bidmc.harvard.edu
authors.forename: Ying
authors.initials: Y
authors.lastname: Dai
authors.forename: Joanne
authors.initials: J
authors.lastname: Clark
authors.forename: Kangni
authors.initials: K
authors.lastname: Zheng
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Kujoth
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.forename: David K
authors.initials: DK
authors.lastname: Simon
mesh_terms: D000375:Aging / Q000187:drug effects*; D000818:Animals; D002452:Cell Count; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D020267:MPTP Poisoning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
chemical_list: D004272:DNA, Mitochondrial; D014446:Tyrosine 3-Monooxygenase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse; D004298:Dopamine