Mitochondrial Dysfunction as a Cause of Axonal Degeneration in Multiple Sclerosis Patients

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 char-acterized 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 postsyn-aptic components of GABAergic neurotransmission and the density of inhibitory interneuron processes also were de-creased in the MS cortex. Interpretation: Our data supports a mechanism whereby reduced ATP production in demy-elinated 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;59:478–48