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

Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD
Ann Neurol. 2006 59 (3): 478-89

PMID: 16392116 · DOI:10.1002/ana.20736

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.

MeSH Terms (25)

Aged Axons Blotting, Western Demyelinating Diseases Electron Transport Chain Complex Proteins Female Glutamate Decarboxylase Humans Immunohistochemistry In Situ Hybridization Isoenzymes Male Microarray Analysis Microscopy, Electron, Transmission Middle Aged Mitochondrial Diseases Multiple Sclerosis Nerve Degeneration Neurofilament Proteins Parvalbumins Postmortem Changes Receptors, GABA-A Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Spinal Cord

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