ORIGINAL PAPER Reduced expression of PGC-1a partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex Maarten E. Witte • Philip G. Nijland • Joost A. R. Drexhage • Wouter Gerritsen • Dirk Geerts • Bert van het Hof • Arie Reijerkerk • Helga E. de Vries • Paul van der Valk • Jack van Horssen Received: 3 July 2012 / Revised: 3 October 2012 / Accepted: 5 October 2012 / Published online: 17 October 2012 Ó Springer-Verlag Berlin Heidelberg 2012 Abstract 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 mitochon- drial 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-1a, a transcriptional co-acti- vator and master regulator of mitochondrial function, was consistently and significantly decreased in pyramidal neu- rons in the deeper layers of MS cortex. Reduced PGC-1a levels coincided with reduced expression of oxidative phosphorylation subunits and a decrease in gene and pro- tein expression of various mitochondrial antioxidants and uncoupling proteins (UCPs) 4 and 5. Short-hairpin RNA- mediated silencing of PGC-1a in a neuronal cell line confirmed that reduced levels of PGC-1a resulted in a decrease in transcription of OxPhos subunits, mitochon- drial antioxidants and UCPs. Moreover, PGC-1a 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-1a decrease. Taken together, our data indicate that reduced neuronal PGC-1a expression in MS cortex partly underlies mitochondrial dysfunction in MS grey matter and thereby contributes to neurodegeneration in MS cortex. Keywords Mitochondria Á Multiple sclerosis Á Neurodegeneration Á PGC-1a Á ROS Introduction Multiple sclerosis (MS) is generally viewed as an auto- immune-mediated disease in which infiltrating macrophages and T-lymphocytes induce focal and diffuse demyelination throughout the brain and spinal cord [15, 22]. In the majority (*85 %) of patients, the disease starts with a relapsing-remitting disease course, but later evolves into progressive disease. Although current available immuno- modulatory therapies are effective in reducing the number of relapses, they ultimately fail to halt disease progression in the progressive phase of the disease [35]. In the pro- gressive stage of MS, widespread axonal degeneration and Electronic supplementary material The online version of this article (doi:10.1007/s00401-012-1052-y) contains supplementary material, which is available to authorized users. M. E. Witte (&) Á P. G. Nijland Á W. Gerritsen Á P. van der Valk Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands e-mail: m.witte@vumc.nl J. A. R. Drexhage Á B. van het Hof Á A. Reijerkerk Á H. E. de Vries Á J. van Horssen Department of Molecular Cell Biology and Immunology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands D. Geerts Department of Pediatric Oncology/Hematology, Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands 123 Acta Neuropathol (2013) 125:231–243 DOI 10.1007/s00401-012-1052-y