Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis

Michael Forte, Bruce G. Gold, Gail Marracci, Priya Chaudhary, Emy Basso, Dustin Johnsen, Xiaolin Yu, Jonathan Fowlkes, Paolo Bernardi, Dennis Bourdette

Research output: Contribution to journalArticle

151 Citations (Scopus)

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 Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)7558-7563
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number18
DOIs
StatePublished - May 1 2007

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Autoimmune Experimental Encephalomyelitis
Multiple Sclerosis
Axons
Animal Models
Inflammation
Reactive Nitrogen Species
cyclophilin D
Demyelinating Diseases
Knockout Mice
Neurodegenerative Diseases
Atrophy
Young Adult
Permeability
Reactive Oxygen Species
Spinal Cord
Mitochondria
Pathology
Neurons
Wounds and Injuries
Brain

Keywords

  • Axonal degeneration
  • Calcium
  • Mitochondria
  • Permeability transition

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. / Forte, Michael; Gold, Bruce G.; Marracci, Gail; Chaudhary, Priya; Basso, Emy; Johnsen, Dustin; Yu, Xiaolin; Fowlkes, Jonathan; Bernardi, Paolo; Bourdette, Dennis.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 18, 01.05.2007, p. 7558-7563.

Research output: Contribution to journalArticle

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