Reduced expression of PGC-1α partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex.
There is growing evidence that mitochondrial dysfunction and associated reactive oxygen species (ROS) formation contribute to neurodegenerative processes in multiple sclerosis (MS). Here, we investigated whether alterations in transcriptional regulators of key mitochondrial proteins underlie mitochondrial dysfunction in MS cortex and contribute to neuronal loss. Hereto, we analyzed the expression of mitochondrial transcriptional (co-)factors and proteins involved in mitochondrial redox balance regulation in normal-appearing grey matter (NAGM) samples of cingulate gyrus and/or frontal cortex from 15 MS patients and nine controls matched for age, gender and post-mortem interval. PGC-1α, a transcriptional co-activator and master regulator of mitochondrial function, was consistently and significantly decreased in pyramidal neurons in the deeper layers of MS cortex. Reduced PGC-1α levels coincided with reduced expression of oxidative phosphorylation subunits and a decrease in gene and protein expression of various mitochondrial antioxidants and uncoupling proteins (UCPs) 4 and 5. Short-hairpin RNA-mediated silencing of PGC-1α in a neuronal cell line confirmed that reduced levels of PGC-1α resulted in a decrease in transcription of OxPhos subunits, mitochondrial antioxidants and UCPs. Moreover, PGC-1α silencing resulted in a decreased mitochondrial membrane potential, increased ROS formation and enhanced susceptibility to ROS-induced cell death. Importantly, we found extensive neuronal loss in NAGM from cingulate gyrus and frontal cortex of MS patients, which significantly correlated with the extent of PGC-1α decrease. Taken together, our data indicate that reduced neuronal PGC-1α expression in MS cortex partly underlies mitochondrial dysfunction in MS grey matter and thereby contributes to neurodegeneration in MS cortex.
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands, m.witte@vumc.nl
Maarten E
ME
Witte
Philip G
PG
Nijland
Joost A R
JA
Drexhage
Wouter
W
Gerritsen
Dirk
D
Geerts
Bert
B
van Het Hof
Arie
A
Reijerkerk
Helga E
HE
de Vries
Paul
P
van der Valk
Jack
J
van Horssen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002452:Cell Count; D002540:Cerebral Cortex / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D005822:Genetic Vectors; D006179:Gyrus Cinguli / Q000473:pathology; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000473:pathology*; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017966:Pyramidal Cells / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014015:Tissue Banks; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014157:Transcription Factors