Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains

Wei Wei,Sarah Ryan,Christopher M Morris,Michael J Keogh,Jonathan Coxhead,Johannes Attems,Olaf Ansorge,Colin Smith,Sara Rollinson,Martin R Turner ,Claire Troakes,Chris-Anne Mckenzie,James Ironside ,Safa Al Sarraj,Helen Griffin,Kevin Talbot,I J Wilson ,Stuart Pickering‐Brown ,Mauro Santibanez‐Koref ,Marzena Kurzawa‐Akanbi ,Patrick F Chinnery

doi:10.1186/s40478-016-0404-6

Abstract

Mitochondria play a key role in common neurodegenerative diseases and contain their own genome: mtDNA. Common inherited polymorphic variants of mtDNA have been associated with several neurodegenerative diseases, and somatic deletions of mtDNA have been found in affected brain regions. However, there are conflicting reports describing the role of rare inherited variants and somatic point mutations in neurodegenerative disorders, and recent evidence also implicates mtDNA levels. To address these issues we studied 1363 post mortem human brains with a histopathological diagnosis of Parkinson’s disease (PD), Alzheimer’s disease (AD), Frontotemporal dementia – Amyotrophic Lateral Sclerosis (FTD-ALS), Creutzfeldt Jacob disease (CJD), and healthy controls. We obtained high-depth whole mitochondrial genome sequences using off target reads from whole exome sequencing to determine the association of mtDNA variation with the development and progression of disease, and to better understand the development of mtDNA mutations and copy number in the aging brain. With this approach, we found a surprisingly high frequency of heteroplasmic mtDNA variants in 32.3% of subjects. However, we found no evidence of an association between rare inherited variants of mtDNA or mtDNA heteroplasmy and disease. In contrast, we observed a reduction in the amount of mtDNA copy in both AD and CJD. Based on these findings, single nucleotide variants of mtDNA are unlikely to play a major role in the pathogenesis of these neurodegenerative diseases, but mtDNA levels merit further investigation.

Highlights

Mitochondria are critical intracellular organelles involved in calcium signaling, lipid biosynthesis, apoptosis [31], and the generation of adenosine triphosphate (ATP) via the mitochondrial respiratory chain [28]
MtDNA deletions accumulate in the ageing brain, reaching higher levels in regions vulnerable to neurodegeneration [3, 26], but evidence describing the accumulation of somatic point mutations or small insertion-deletion mutations is less compelling, with conflicting reports in the literature [6, 20]
We found no evidence that rare inherited polymorphisms or mtDNA heteroplasmy contributes to the pathogenesis of neurodegenerative diseases, differences in mtDNA content provide a clue to disease mechanism in Alzheimer’s disease (AD) and Creutzfeldt Jacob disease (CJD)

Summary

Introduction

Mitochondria are critical intracellular organelles involved in calcium signaling, lipid biosynthesis, apoptosis [31], and the generation of adenosine triphosphate (ATP) via the mitochondrial respiratory chain [28]. Over the last decade it has become clear that mitochondria play a key role in the pathogenesis of common neurodegenerative disorders. Mitochondria contain their own 16.5 kb circular mitochondria genome (mtDNA), which. In addition to maternally inherited polymorphisms, acquired somatic mutations of mtDNA have been associated with neurodegenerative disorders. MtDNA deletions accumulate in the ageing brain, reaching higher levels in regions vulnerable to neurodegeneration [3, 26], but evidence describing the accumulation of somatic point mutations or small insertion-deletion mutations (indels) is less compelling, with conflicting reports in the literature [6, 20]. Several recent studies have described abnormal amounts of mtDNA both in cerebrospinal fluid or the brains of patients with neurodegenerative diseases [23, 24], but only in a limited number of individuals

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Discussion

Conclusion