title: Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.
abstract: Multiple sclerosis (MS) is the leading cause of neurological disability in young adults, affecting some two million people worldwide. Traditionally, MS has been considered a chronic, inflammatory disorder of the central white matter in which ensuing demyelination results in physical disability [Frohman EM, Racke MK, Raine CS (2006) N Engl J Med 354:942-955]. More recently, MS has become increasingly viewed as a neurodegenerative disorder in which neuronal loss, axonal injury, and atrophy of the CNS lead to permanent neurological and clinical disability. Although axonal pathology and loss in MS has been recognized for >100 years, very little is known about the underlying molecular mechanisms. Progressive axonal loss in MS may stem from a cascade of ionic imbalances initiated by inflammation, leading to mitochondrial dysfunction and energetic deficits that result in mitochondrial and cellular Ca2+ overload. In a murine disease model, experimental autoimmune encephalomyelitis (EAE) mice lacking cyclophilin D (CyPD), a key regulator of the mitochondrial permeability transition pore (PTP), developed EAE, but unlike WT mice, they partially recovered. Examination of the spinal cords of CyPD-knockout mice revealed a striking preservation of axons, despite a similar extent of inflammation. Furthermore, neurons prepared from CyPD-knockout animals were resistant to reactive oxygen and nitrogen species thought to mediate axonal damage in EAE and MS, and brain mitochondria lacking CyPD sequestered substantially higher levels of Ca2+. Our results directly implicate pathological activation of the mitochondrial PTP in the axonal damage occurring during MS and identify CyPD, as well as the PTP, as a potential target for MS neuroprotective therapies.
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA. forte@ohsu.edu
authors.forename: Michael
authors.initials: M
authors.lastname: Forte
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Gold
authors.forename: Gail
authors.initials: G
authors.lastname: Marracci
authors.forename: Priya
authors.initials: P
authors.lastname: Chaudhary
authors.forename: Emy
authors.initials: E
authors.lastname: Basso
authors.forename: Dustin
authors.initials: D
authors.lastname: Johnsen
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Yu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fowlkes
authors.forename: Micha
authors.initials: M
authors.lastname: Rahder
authors.forename: Katie
authors.initials: K
authors.lastname: Stem
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Dennis
authors.initials: D
authors.lastname: Bourdette
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology* / Q000473:pathology*; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D004789:Enzyme Activation; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D009584:Nitrogen / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D017382:Reactive Oxygen Species; D021983:Cyclophilins; D009584:Nitrogen