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Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients
Author(s) -
Dutta Ranjan,
McDonough Jennifer,
Yin Xinghua,
Peterson John,
Chang Ansi,
Torres Thalia,
Gudz Tatyana,
Macklin Wendy B.,
Lewis David A.,
Fox Robert J.,
Rudick Richard,
Mirnics Karoly,
Trapp Bruce D.
Publication year - 2006
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20736
Subject(s) - neurotransmission , neuroprotection , biology , neuroscience , mitochondrial respiratory chain , mitochondrion , motor cortex , axonal degeneration , degeneration (medical) , multiple sclerosis , medicine , pathology , microbiology and biotechnology , stimulation , receptor , biochemistry , immunology
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.InterpretationOur 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