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.

EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

“…Recently, it was shown that when mice null for the cyclophilin D gene were induced with EAE, they recovered earlier than their wild-type counterparts (Forte et al, 2007). Although these null mice had similar inflammatory scores as wild-type controls, they had more spared axons, which were attributed to the neurons in cyclophilin D null mice being more resistant to the reactive oxygen and nitrogen species encountered in EAE (Forte et al, 2007).…”

Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition

“…More specific evidence for the involvement of mPT in neurological disorders has more recently been obtained with genetically modified mice lacking cyclophilin D, an important modulator of the mPT and the mitochondrial receptor for CsA. The knock-out mediated resistance to cerebral focal ischemia, experimental multiple sclerosis and as well cardiac ischemia [46][47][48].…”

A recoverable state of axon injury persists for hours after spinal cord contusion in vivo

“…Given the critical role of calcium accumulations in contused axons, it is important to consider where the intra-axonal calcium is coming from and which downstream mechanisms it initiates. In vitro and in a multitude of neurological conditions, including trauma, ischaemia, inflammation and degeneration 12,26 , a broad range of mechanisms have been implicated as sources for elevated axonal calcium, including extracellular sources (for example, voltage-gated ion channels [17][18][19] , the plasma membrane sodiumcalcium exchanger [20][21][22] , the acid sensing ion channel 27 or nodal glutamate receptors 23 ), as well as intracellular stores (such as mitochondria 28 or the endoplasmic reticulum 29 ). Our in vivo analysis now indicates that mechanoporation, that is, the formation of pores in the plasma membrane as first described after diffused brain injury 24 , is a dominant source of calcium influx at least in the first hours after contusion.…”