Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients

Ranjan Dutta, Jennifer McDonough, Xinghua Yin, John Peterson, Ansi Chang, Thalia Torres, Tatyana Gudz, Wendy B. Macklin, David A. Lewis, Robert J. Fox, Richard Rudick, Karoly Mirnics, Bruce D. Trapp

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Abstract

Objective: 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. Methods: 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. Results: 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. Interpretation: 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.

Original languageEnglish (US)
Pages (from-to)478-489
Number of pages12
JournalAnnals of Neurology
Volume59
Issue number3
DOIs
StatePublished - Mar 1 2006

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ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

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., & Trapp, B. D. (2006). Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Annals of Neurology, 59(3), 478-489. https://doi.org/10.1002/ana.20736