Somatic mitochondrial DNA mutations in early Parkinson and incidental Lewy body disease

Abstract

Somatic mutations in mitochondrial DNA (mtDNA) are hypothesized to play a role in Parkinson disease (PD), but large increases in mtDNA mutations have not previously been found in PD, potentially because neurons with high mutation levels degenerate and thus are absent in late stage tissue. To address this issue, we studied early stage PD cases and cases of incidental Lewy body disease (ILBD), which is thought to represent presymptomatic PD. We show for the first time that mtDNA mutation levels in substantia nigra neurons are significantly elevated in this group of early PD and ILBD cases.

Figure 1. Somatic mitochondrial DNA point mutation levels in controls, early PD+ILBD, and late PD

DNA was extracted from groups of up to 50 neurons or glia isolated by laser capture microdissection; mtDNA regions of interest (D-loop or ND5) were PCR amplified; and point mutations were identified by cloning and sequencing as previously described.^{, ,} Bars and error bars indicate means and standard errors. To account for the 3 pairwise comparisons among disease states (early PD+ILBD vs control, early PD+ILBD vs late PD, control vs late PD), significance was set at p=0.05/3. A. Overall somatic point mutation levels in SN neurons. *p=0.0001, **p=0.0003. B. Levels of G→T or C→A transversions in SN neurons. *p<0.0001, **p=0.0006. C. Overall somatic point mutation levels in SN glia. D. Levels of G→T or C→A transversions in SN glia. E. mtDNA mutation levels in SN neurons vs glia.