Research: Nerve energy loss and damage

Witte ME, Nijland PG, Drexhage JA, Gerritsen W, Geerts D, van Het Hof B, Reijerkerk A, de Vries HE, van der Valk P, van Horssen J. Reduced expression of PGC-1α partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex. Acta Neuropathol. 2012 Oct 17. [Epub ahead of print]

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.

Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a member of a family of transcription coactivators that plays a central role in the regulation of cellular energy metabolism. This is involved in the production of energy in the powerhouses of cells (mitochondria). In certain areas of the brain, this is reduced and so the interfer is that this low level may contribute to an energy deficit in nerves that can lead to nerve damage that leads to progression. Thus more evidence that alterations in cellular energy is a problem, but what causes this. The answer is probably demyelination somewhere in the nerve circuitary so that it reduces energy in normal appearing nerves such that they are vulnerable to damage.

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