ABSTRACT
Axonal degeneration is a major determinant of permanent neurological impairment during multiple sclerosis (MS). Due to the variable course of clinical disease and the heterogeneity of MS lesions, the mechanisms governing axonal degeneration may differ between disease stages. While the etiology of MS remains elusive, there now exist potential prognostic biomarkers that can predict the conversion to clinically definite MS. Specialized imaging techniques identifying axonal injury and drop-out are becoming established in clinical practice as a predictive measure of MS progression, such as optical coherence tomography (OCT) or diffusion tensor imaging (DTI). However, these imaging techniques are still being debated as predictive biomarkers since controversy surrounds their lesion-specific association with expanded disability status scale (EDSS). A more promising diagnostic measure of axonal degeneration has been argued for the detection of reduced N-acetyl aspartate (NAA) and Creatine ratios via magnetic resonance spectroscopic (MRS) imaging, but again fail with its specificity for predicting actual axonal degeneration. Greater accuracy of predictive biomarkers is therefore warranted and may include CSF neurofilament light chain (NF-L) and neurofilament heavy chain (NF-H) levels, for progressive MS. Furthermore, defining the molecular mechanisms that occur during the neurodegenerative changes in the various subgroups of MS may in fact prove vital for the future development of efficacious neuroprotective therapies. The clinical translation of a combined Na+ and Ca2+ channel blocker may lead to the establishment of a bona fide neuroprotective agent for the treatment of progressive MS. However, more specific therapeutic targets to limit axonal damage in MS need investigation and may include such integral axonal proteins such as the collapsin response mediator protein-2 (CRMP-2), a molecule which upon post-translational modification may propagate axonal degeneration in MS. In this review, we discuss the current clinical determinants of axonal damage in MS and consider the cellular and molecular mechanisms that may initiate these neurodegenerative changes. In particular we highlight the therapeutic candidates that may formulate novel therapeutic strategies to limit axonal degeneration and EDSS during progressive MS.
Subject(s)
Axons/pathology , Disabled Persons , Multiple Sclerosis/complications , Nerve Degeneration , Animals , Humans , Nerve Degeneration/diagnosis , Nerve Degeneration/etiology , Nerve Degeneration/prevention & control , Predictive Value of TestsABSTRACT
Multiple sclerosis involves demyelination and axonal degeneration of the central nervous system. The molecular mechanisms of axonal degeneration are relatively unexplored in both multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis. We previously reported that targeting the axonal growth inhibitor, Nogo-A, may protect against neurodegeneration in experimental autoimmune encephalomyelitis; however, the mechanism by which this occurs is unclear. We now show that the collapsin response mediator protein 2 (CRMP-2), an important tubulin-associated protein that regulates axonal growth, is phosphorylated and hence inhibited during the progression of experimental autoimmune encephalomyelitis in degenerating axons. The phosphorylated form of CRMP-2 (pThr555CRMP-2) is localized to spinal cord neurons and axons in chronic-active multiple sclerosis lesions. Specifically, pThr555CRMP-2 is implicated to be Nogo-66 receptor 1 (NgR1)-dependent, since myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced NgR1 knock-out (ngr1(-)(/)(-)) mice display a reduced experimental autoimmune encephalomyelitis disease progression, without a deregulation of ngr1(-)(/)(-) MOG(35-55)-reactive lymphocytes and monocytes. The limitation of axonal degeneration/loss in experimental autoimmune encephalomyelitis-induced ngr1(-)(/)(-) mice is associated with lower levels of pThr555CRMP-2 in the spinal cord and optic nerve during experimental autoimmune encephalomyelitis. Furthermore, transduction of retinal ganglion cells with an adeno-associated viral vector encoding a site-specific mutant T555ACRMP-2 construct, limits optic nerve axonal degeneration occurring at peak stage of experimental autoimmune encephalomyelitis. Therapeutic administration of the anti-Nogo(623-640) antibody during the course of experimental autoimmune encephalomyelitis, associated with an improved clinical outcome, is demonstrated to abrogate the protein levels of pThr555CRMP-2 in the spinal cord and improve pathological outcome. We conclude that phosphorylation of CRMP-2 may be downstream of NgR1 activation and play a role in axonal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Blockade of Nogo-A/NgR1 interaction may serve as a viable therapeutic target in multiple sclerosis.
Subject(s)
Axons/metabolism , Encephalomyelitis, Autoimmune, Experimental/complications , Intercellular Signaling Peptides and Proteins/metabolism , Multiple Sclerosis/pathology , Nerve Degeneration/metabolism , Nerve Tissue Proteins/metabolism , Adult , Analysis of Variance , Animals , Antibodies/therapeutic use , Axons/pathology , Axons/ultrastructure , CD3 Complex/metabolism , Cell Line, Tumor , Demyelinating Diseases/etiology , Demyelinating Diseases/metabolism , Demyelinating Diseases/pathology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/immunology , Female , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/deficiency , GPI-Linked Proteins/immunology , Gene Expression Regulation/genetics , Glycoproteins/adverse effects , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Immunoprecipitation , Intercellular Signaling Peptides and Proteins/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Multiple Sclerosis/complications , Mutation/genetics , Myelin Proteins/antagonists & inhibitors , Myelin Proteins/deficiency , Myelin Proteins/immunology , Myelin-Oligodendrocyte Glycoprotein , Nerve Degeneration/etiology , Nerve Tissue Proteins/genetics , Neuroblastoma/pathology , Neurofilament Proteins/metabolism , Nogo Receptor 1 , Optic Nerve/metabolism , Optic Nerve/pathology , Peptide Fragments/adverse effects , Phosphorylation , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Cell Surface/deficiency , Receptors, Cell Surface/immunology , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/pathologyABSTRACT
The family of the collapsin response mediator proteins (CRMPs) plays a significant physiological role in neuronal cell bodies and axons within the integrated mammalian central nervous system (CNS). Trauma-induced damage to the CNS results in variable degrees of axonal degeneration, and this may lead to neuronal cell death in key grey matter regions. Site-specific phosphorylation of certain CRMPs has been associated with trauma-induced axonal degeneration. Moreover, recent data implicate the pro-apoptotic, calcium-dependent protease calpain as a key initiator of CRMP cleavage. The primary cleavage product of injury-induced neuronal calpain activation is a C-terminus truncated 55- to 58-kDa form of CRMP, which may exert its effects within the cytoplasm and axonal core, or alternatively through its translocation into the nucleus, initiating neuronal cell death. The precise structure of cleaved CRMP has yet to be elucidated, as is the reason for nuclear translocation. Once the crystal structure of the cytoplasmic and nuclear-translocated forms of CRMPs is determined, a greater molecular understanding of why these forms can initiate neurodegeneration following CNS injury will be established. Such information will be particularly informative in the design of inhibitors of specific protein-protein interaction sites between cleaved CRMP and vital cytosolic or nuclear molecules.