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.