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Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2007 May 01; Vol. 104 (18), pp. 7558-63. Date of Electronic Publication: 2007 Apr 26. - Publication Year :
- 2007
-
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.
- Subjects :
- Animals
Brain metabolism
Cells, Cultured
Peptidyl-Prolyl Isomerase F
Cyclophilins deficiency
Cyclophilins genetics
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental genetics
Enzyme Activation
Inflammation enzymology
Inflammation genetics
Inflammation pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria genetics
Mitochondria metabolism
Multiple Sclerosis genetics
Nitrogen metabolism
Phosphorylation
Reactive Oxygen Species metabolism
Axons enzymology
Axons pathology
Cyclophilins metabolism
Encephalomyelitis, Autoimmune, Experimental enzymology
Encephalomyelitis, Autoimmune, Experimental pathology
Multiple Sclerosis enzymology
Multiple Sclerosis pathology
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 104
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 17463082
- Full Text :
- https://doi.org/10.1073/pnas.0702228104