title: Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Dutta
authors.forename: Jennifer
authors.initials: J
authors.lastname: McDonough
authors.forename: Xinghua
authors.initials: X
authors.lastname: Yin
authors.forename: John
authors.initials: J
authors.lastname: Peterson
authors.forename: Ansi
authors.initials: A
authors.lastname: Chang
authors.forename: Thalia
authors.initials: T
authors.lastname: Torres
authors.forename: Tatyana
authors.initials: T
authors.lastname: Gudz
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Macklin
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fox
authors.forename: Richard
authors.initials: R
authors.lastname: Rudick
authors.forename: Karoly
authors.initials: K
authors.lastname: Mirnics
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Trapp
mesh_terms: D000368:Aged; D001369:Axons / Q000473:pathology* / Q000648:ultrastructure; D015153:Blotting, Western / Q000379:methods; D003711:Demyelinating Diseases / Q000209:etiology / Q000473:pathology; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000473:pathology*; D009103:Multiple Sclerosis / Q000473:pathology* / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000209:etiology* / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000096:biosynthesis; D011963:Receptors, GABA-A / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure
chemical_list: D045222:Electron Transport Chain Complex Proteins; D007527:Isoenzymes; D016900:Neurofilament Proteins; D010320:Parvalbumins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1