R.D. and J.M. contributed equally to this study.
Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients
Version of Record online: 3 JAN 2006
Copyright © 2005 American Neurological Association
Annals of Neurology
Volume 59, Issue 3, pages 478–489, March 2006
How to Cite
Dutta, R., McDonough, J., Yin, X., Peterson, J., Chang, A., Torres, T., Gudz, T., Macklin, W. B., Lewis, D. A., Fox, R. J., Rudick, R., Mirnics, K. and Trapp, B. D. (2006), Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol., 59: 478–489. doi: 10.1002/ana.20736
- Issue online: 17 FEB 2006
- Version of Record online: 3 JAN 2006
- Manuscript Revised: 6 OCT 2005
- Manuscript Accepted: 6 OCT 2005
- Manuscript Received: 16 AUG 2005
- NIH (National Institute on Neurological Disorders and Stroke). Grant Numbers: NS35058, NS38667
- National Multiple Sclerosis Society postdoctoral fellowship
Degeneration of chronically demyelinated axons is a major cause of irreversible neurological disability in multiple sclerosis (MS) patients. Development of neuroprotective therapies will require elucidation of the molecular mechanisms by which neurons and axons degenerate.
We report ultrastructural changes that support Ca2+-mediated destruction of chronically demyelinated axons in MS patients. We compared expression levels of 33,000 characterized genes in postmortem motor cortex from six control and six MS brains matched for age, sex, and postmortem interval. As reduced energy production is a major contributor to Ca2+-mediated axonal degeneration, we focused on changes in oxidative phosphorylation and inhibitory neurotransmission.
Compared with controls, 488 transcripts were decreased and 67 were increased (p < 0.05, 1.5-fold) in the MS cortex. Twenty-six nuclear-encoded mitochondrial genes and the functional activities of mitochondrial respiratory chain complexes I and III were decreased in the MS motor cortex. Reduced mitochondrial gene expression was specific for neurons. In addition, pre-synaptic and postsynaptic components of GABAergic neurotransmission and the density of inhibitory interneuron processes also were decreased in the MS cortex.
Our data supports a mechanism whereby reduced ATP production in demyelinated segments of upper motor neuron axons impacts ion homeostasis, induces Ca2+-mediated axonal degeneration, and contributes to progressive neurological disability in MS patients. Ann Neurol 2006