Somatic mtDNA variation is an important component of Parkinson's disease

Abstract

There is a growing body of evidence linking mitochondrial dysfunction, mediated either through inherited mitochondrial DNA (mtDNA) variation or mitochondrial proteomic deficit, to Parkinson's disease (PD). Yet, despite this, the role of somatic mtDNA point mutations and specifically point-mutational burden in PD is poorly understood. Here, we take advantage of recent technical and methodological advances to examine the role of age-related and acquired mtDNA mutation in the largest study of mtDNA in postmortem PD tissue to date. Our data show that PD patients suffer an increase in mtDNA mutational burden in, but no limited to, the substantia nigra pars compacta when compared to matched controls. This mutational burden appears increased in genes encoding cytochrome c oxidase, supportive of previous protein studies of mitochondrial dysfunction in PD. Accepting experimental limitations, our study confirms the important role of age-related mtDNA point mutation in the etiology of PD, moreover, by analyzing 2 distinct brain regions, we are able to show that PD patient brains are more vulnerable to mtDNA mutation overall.

Keywords: Mitochondria; Neurodegeneration; Parkinson's disease; Somatic mutation.

Fig. 1

The upper panel shows the comparative mean number of (A) total variants, (B) homoplasmic variants, and (C) heteroplasmic variants stratified by status and tissue origin; where PD = shaded boxes and controls = unshaded boxes. Statistical comparison by Mann-Whitney confirmed a higher heteroplasmic mutational burden in PD patients in both SN and FC (*p = 0.012 and **p = 0.005). The lower panel shows further stratification of heteroplasmic variant burden, limiting to nonsynonomous variants in SN (D) and FC (E) only; where PD = shaded boxes and controls = unshaded boxes. Statistical comparison by Mann-Whitney confirmed a significant (P ≤ 0.0001, starred) overrepresentation of heteroplasmic nonsynonymous variants in PD in MTCOX1, MTCOX2 in SN, and MTCYTB in both SN and FC (error bars indicate 95% confidence intervals). Abbreviations: SN = substantia nigra; FC = frontal cortex; PD, Parkinson's disease; COX, cytochrome c oxidase; ATP, adenosine triphosphate.

Fig. 2

The left panel shows the comparative distribution of (A) de novo SNpc variants; (B) variants lost in SNpc compared to FC; (C) negative-heteroplasmic shifts (ΔhetFC > SNpc); and (D) positive-heteroplasmic shifts (ΔhetFC < SNpc) between PD cases (shaded) and controls (unshaded) using Mann-Whitney nonparametric testing. The middle panel shows the percentage breakdown by variant type, and the right panels shows the mtDNA locus distribution of identified heteroplasmic nonsynonymous variants, where * Pearson's chi-squared P ≤ 0.05 when comparing PD cases and controls. Abbreviations: SNpc, substantia nigra pars compacta; FC, frontal cortex; PD, Parkinson's disease; mtDNA, mitochondrial DNA; ATP, adenosine triphosphate.