Impaired regulation of electron transport chain subunit genes by nuclear respiratory factor 2 in multiple sclerosis.
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease. Recently, decreased expression of nuclear encoded electron transport chain genes was found in neurons in MS cortex. To understand the transcriptional mechanisms responsible for the coordinate down regulation of these genes, we performed electrophoretic mobility shifts with nuclear extracts isolated from gray matter from nonlesion areas of postmortem MS and control cortex. Nine tissue blocks from eight different MS brains and six matched control blocks from five control brains were analyzed. We identified a decrease in a transcription factor complex containing nuclear respiratory factor 2 (NRF-2) in nuclear extracts isolated from MS cortex. This decrease is correlated with decreased expression of electron transport chain subunit genes and increased oxidative damage measured by increased anti-nitrotyrosine immunoreactivity. We conclude that in MS cortex a chronic increase in oxidative stress leads to aberrant regulation of transcription of genes involved in energy metabolism.
Pandit
Ashish
A
School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA.
Vadnal
Jonathan
J
Houston
Sara
S
Freeman
Ernest
E
McDonough
Jennifer
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D051268:GA-Binding Protein Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D045222:Electron Transport Chain Complex Proteins; D051268:GA-Binding Protein Transcription Factor; C002744:3-nitrotyrosine; D014443:Tyrosine