Reference : Mitochondrial DNA depletion in respiratory chain-deficient Parkinson disease neurons.
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/10993/24458
Mitochondrial DNA depletion in respiratory chain-deficient Parkinson disease neurons.
English
Grünewald, Anne mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Rygiel, Karolina A. [> >]
Hepplewhite, Philippa D. [> >]
Morris, Christopher M. [> >]
Picard, Martin [> >]
Turnbull, Doug M. [> >]
Mar-2016
Annals of Neurology
Wiley Liss, Inc.
79
3
366-378
Yes (verified by ORBilu)
International
0364-5134
1531-8249
New York
NY
[en] sporadic Parkinson's disease ; mitochondrial genome ; respiratory chain ; postmortem ; substantia nigra
[en] OBJECTIVE: To determine the extent of respiratory chain abnormalities and investigate the contribution of mitochondrial DNA (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 PCR assay.
RESULTS: While 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 single-cell level, CI and II deficiencies were correlated in patients. The CI deficit 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 complex I 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. This article is protected by copyright. All rights reserved.
Researchers ; Students
http://hdl.handle.net/10993/24458
10.1002/ana.24571
http://onlinelibrary.wiley.com/doi/10.1002/ana.24571/epdf
(c) 2015 American Neurological Association.
FnR ; FNR9631103 > Anne Grünewald > Model IPD > Modelling Idiopathic Parkinson’S Disease-Associated Somatic Variation In Dopaminergic Neurons > 01/01/2016 > 31/12/2020 > 2015

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