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Lookup NU author(s): Dr Anne Grunewald, Dr Karolina Rygiel, Philippa Hepplewhite, Dr Christopher Morris, Dr Martin Picard, Emeritus Professor Doug Turnbull
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Objective: To determine the extent of respiratory chain abnormalities and investigate the contribution of mtDNA to the loss of respiratory chain complexes (CI-IV) in the substantia nigra (SN) of idiopathic Parkinson disease (IPD) patients at the single-neuron level.Methods: Multiple-label immunofluorescence was applied to postmortem sections of 10 IPD patients and 10 controls to quantify the abundance of CI-IV subunits (NDUFB8 or NDUFA13, SDHA, UQCRC2, and COXI) and mitochondrial transcription factors (TFAM and TFB2M) relative to mitochondrial mass (porin and GRP75) in dopaminergic neurons. To assess the involvement of mtDNA in respiratory chain deficiency in IPD, SN neurons, isolated with laser-capture microdissection, were assayed for mtDNA deletions, copy number, and presence of transcription/replication-associated 7S DNA employing a triplex real-time polymerase chain reaction (PCR) assay.Results: Whereas mitochondrial mass was unchanged in single SN neurons from IPD patients, we observed a significant reduction in the abundances of CI and II subunits. At the single-cell level, CI and II deficiencies were correlated in patients. The CI deficiency concomitantly occurred with low abundances of the mtDNA transcription factors TFAM and TFB2M, which also initiate transcription-primed mtDNA replication. Consistent with this, real-time PCR analysis revealed fewer transcription/replication-associated mtDNA molecules and an overall reduction in mtDNA copy number in patients. This effect was more pronounced in single IPD neurons with severe CI deficiency.Interpretation: Respiratory chain dysfunction in IPD neurons not only involves CI, but also extends to CII. These deficiencies are possibly a consequence of the interplay between nDNA and mtDNA-encoded factors mechanistically connected via TFAM.
Author(s): Grunewald A, Rygiel KA, Hepplewhite PD, Morris CM, Picard M, Turnbull DM
Publication type: Article
Publication status: Published
Journal: Annals of Neurology
Year: 2016
Volume: 79
Issue: 3
Pages: 366-378
Print publication date: 01/03/2016
Online publication date: 28/01/2016
Acceptance date: 24/11/2015
Date deposited: 16/05/2016
ISSN (print): 0364-5134
ISSN (electronic): 1531-8249
Publisher: Wiley-Blackwell Publishing Ltd.
URL: http://dx.doi.org/10.1002/ana.24571
DOI: 10.1002/ana.24571
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