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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.
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
URL: http://dx.doi.org/10.1523/JNEUROSCI.3525-12.2013
DOI: 10.1523/JNEUROSCI.3525-12.2013
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