Defective Mitochondrial DNA Homeostasis in the Substantia Nigra in Parkinson Disease

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Nov 23

PMID 27874000

Citations 133

Authors

Christian Dolle

Irene Flones

Gonzalo S Nido

Hrvoje Miletic

Nelson Osuagwu

Stine Kristoffersen

Peer K Lilleng

Jan Petter Larsen

Ole-Bjorn Tysnes

Kristoffer Haugarvoll

Laurence A Bindoff

Charalampos Tzoulis

Affiliations

Soon will be listed here.

Abstract

Increased somatic mitochondrial DNA (mtDNA) mutagenesis causes premature aging in mice, and mtDNA damage accumulates in the human brain with aging and neurodegenerative disorders such as Parkinson disease (PD). Here, we study the complete spectrum of mtDNA changes, including deletions, copy-number variation and point mutations, in single neurons from the dopaminergic substantia nigra and other brain areas of individuals with Parkinson disease and neurologically healthy controls. We show that in dopaminergic substantia nigra neurons of healthy individuals, mtDNA copy number increases with age, maintaining the pool of wild-type mtDNA population in spite of accumulating deletions. This upregulation fails to occur in individuals with Parkinson disease, however, resulting in depletion of the wild-type mtDNA population. By contrast, neuronal mtDNA point mutational load is not increased in Parkinson disease. Our findings suggest that dysregulation of mtDNA homeostasis is a key process in the pathogenesis of neuronal loss in Parkinson disease.

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