Relationships among molecular genetic and respiratory properties of Parkinson's disease cybrid cells show similarities to Parkinson's brain tissues.
We have studied sporadic Parkinson's disease (sPD) from expression of patient mitochondrial DNA (mtDNA) in neural cells devoid of their own mtDNA, the "cybrid" model. In spite of reproducing several properties of sPD brain, it remains unclear whether sPD cybrid cells reflect more complex sPD brain bioenergetic pathophysiology. We characterized and correlated respiration of intact sPD cybrid cells with electron transport chain (ETC) protein assembly, complex I ETC gene expression and ETC protein levels in sPD brain. We also assayed expression for multiple ETC genes coded by mtDNA and nuclear DNA (nDNA) in sPD cybrid cells and brain. sPD cybrid cells have reduced levels of mtDNA genes, variable compensatory normalization of mitochondrial gene expression and show robust correlations with mitochondrial ETC gene expression in sPD brains. Relationships among ETC protein levels predict impaired complex I-mediated respiration in sPD brain. That sPD cybrid cells and sPD brain samples show very correlated regulation of nDNA and mtDNA ETC transcriptomes suggests similar bioenergetic physiologies. We propose that further insights into sPD pathogenesis will follow elucidation of mechanisms leading to reduced mtDNA gene levels in sPD cybrids. This will require characterization of the abnormalities and dynamics of mtDNA changes propagated through sPD cybrids over time.
Borland
M Kathleen
MK
Center for the Study of Neurodegenerative Diseases, University of Virginia, Charlottesville, Virginia, USA.
Mohanakumar
K P
KP
Rubinstein
Jeremy D
JD
Keeney
Paula M
PM
Xie
Jing
J
Capaldi
Roderick
R
Dunham
Lisa D
LD
Trimmer
Patricia A
PA
Bennett
James P
JP
D001921:Brain / Q000378:metabolism*; D019069:Cell Respiration; D004272:DNA, Mitochondrial / Q000235:genetics; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006822:Hybrid Cells; D008967:Molecular Biology; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*
D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I