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The Impact of Pathogenic Mitochondrial DNA Mutations on Substantia Nigra Neurons

Lookup NU author(s): Dr Amy Reeve, Dr Martin Meagher, Dr Nichola Lax, Dr Eve Cosgrave, Philippa Hepplewhite, Dr Evelyn Jaros, Emeritus Professor Doug Turnbull



Mitochondrial defects within substantia nigra (SN) neurons are implicated in the pathogenesis of Parkinson's disease. SN neurons show increased mitochondrial defects, mitochondrial DNA deletion levels, and susceptibility to such dysfunction, although the role of mitochondria in neuronal degeneration remains uncertain. In this study, we addressed this important question by exploring changes within the mitochondria of SN neurons from patients with primary mitochondrial diseases to determine whether mitochondrial dysfunction leads directly to neuronal cell loss. We counted the pigmented neurons and quantified mitochondrial respiratory activity, deficiencies in mitochondrial proteins, and the percentage of pathogenic mutations in single neurons. We found evidence of defects of both complex I and complex IV of the respiratory chain in all patients. We found that marked neuronal cell loss was only observed in a few patients with mitochondrial disease and that all these patients had mutations in polymerase gamma (POLG), which leads to the formation of multiple mitochondrial DNA deletions over time, similar to aging and Parkinson's disease. Interestingly, we detected alpha-synuclein pathology in two mitochondrial patients with POLG mutations. Our observations highlight the complex relationship between mitochondrial dysfunction and the susceptibility of SN neurons to degeneration and alpha-synuclein pathology. Our finding that the loss of SN neurons was only severe in patients with POLG mutations suggests that acquired mitochondrial defects may be less well tolerated by SN neurons than by inherited ones.

Publication metadata

Author(s): Reeve A, Meagher M, Lax N, Simcox E, Hepplewhite P, Jaros E, Turnbull D

Publication type: Article

Publication status: Published

Journal: Journal of Neuroscience

Year: 2013

Volume: 33

Issue: 26

Pages: 10790-10801

Print publication date: 26/06/2013

Date deposited: 24/07/2014

ISSN (print): 0270-6474

ISSN (electronic): 1529-2401

Publisher: Society for Neuroscience


DOI: 10.1523/JNEUROSCI.3525-12.2013


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Funder referenceFunder name
Economic and Social Research Council
Engineering and Physical Sciences Research Council
Newcastle University Centre for Brain Ageing and Vitality
Alzheimer's Research Trust
Alzheimer's Society
Biotechnology and Biological Sciences Research Council
Brains for Dementia Research Project
National Institute for Health Research Newcastle Biomedical Research Centre in Ageing and Chronic Diseases
G0700718Medical Research Council
G0400074Medical Research Council
G906919The Wellcome Trust Centre for Mitochondrial Research