Relationships among molecular genetic and respiratory properties of Parkinson's disease cybrid cells show similarities to Parkinson's brain tissues

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1792

Article

Borland, M. Kathleen^1,2  Mohanakumar, K. P.³  Rubinstein, Jeremy D.^1,2  Keeney, Paula M.^1,2  Xie, Jing⁴  Capaldi, Roderick⁴  Dunham, Lisa D.^1,2  Trimmer, Patricia A.^1,2  Bennett, James P., Jr.^1,2 

[1] Univ Virginia, Ctr Study Neurodegenerat Dis, Charlottesville, VA USA

[2] Univ Virginia, Morris Udall Parkinsons Dis Res Ctr Excellence, Charlottesville, VA USA

[3] Indian Inst Chem Biol, Lab Expt & Clin Neurosci, Div Cell Biol & Physiol, Kolkata 700032, W Bengal, India

[4] Mitosciences Inc, Eugene, OR USA

关键词: Parkinson's disease;    Mitochondria;    Cybrid;    Respiration;    Complex I;    Gene expression;   

DOI  :  10.1016/j.bbadis.2008.09.014

来源: Elsevier

【 摘 要 】

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. (C) 2008 Elsevier B.V. All rights reserved.

【 授权许可】

Free