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Blocking CRMP2 SUMOylation reverses neuropathic pain

Molecular Psychiatry volume 23, pages 2119–2121 (2018)Cite this article

Collapsin response mediator proteins 1−5 (CRMPs1−5) are a family of cytosolic proteins that coordinate neuronal migration, axonal guidance, dendritic organization, dendritic spine development and synaptic plasticity (reviewed in Khanna et al.1and Quach et al.2). Members of the CRMP family are reported to be involved in the pathogenesis of various neuronal disorders. For instance, proteomic, genomic and translational approaches linked the CRMP1 gene with chronic, negative symptoms of schizophrenia and severe major depression.3 Mice lacking CRMP1 manifest hyperactivity, impaired learning and memory, and impaired prepulse inhibition behavioral abnormalities related to schizophrenia.4 Genetic association and linkage studies pointed to CRMP2 as a liability gene for schizophrenia, autism, alcohol dependence, depression and bipolar disorders.5,6,7,8,9,10 Mice with brain-specific Crmp2 deletion exhibited behavioral deficits in locomotor activity, sensorimotor gating, social behavior, and spatial learning and memory.11 Maternal autoantibodies against CRMP1 and CRMP2 were found in children with autism spectrum disorders that displayed core deficits in communication and reciprocal social interaction as well as repetitive or stereotypical behaviors.12 CRMP3-deficient mice display significant decreases in dendritic length and branching points, and an abnormal undulation of apical primary dendrites; these findings are recapitulated in the brain of Down syndrome where the expression of CRMP3 gene is also impaired.13 Little is known about the relationship between CRMP4 and neuropsychiatric disorders. However, mice lacking CRMP4 manifest impaired olfactory function and hyperactivity in the olfactory bulb and have increased levels of ionotropic glutamate receptors GluRs 1 and 2, which have been implicated in autism spectrum disorders and schizophrenia.14 CRMP5 knockout mice implicate this protein in dendritic development and synaptic plasticity in cerebellar purkinje cells,15 and CRMP5 autoantibodies were reported in patients with paraneoplastic neurological syndrome characterized by cerebellar ataxia and chorea. Therefore, understanding CRMP signaling has significant clinical implications.

CRMPs undergo several post-translational modifications (PTMs) that are hypothesized to play a critical role in codifying its functions. For example, CRMP2 is subject to phosphorylation at multiple sites, SUMOylation (addition of small ubiquitin-like modifier (SUMO)), O-GlyNAcylation (addition of β-N-acetyl-d-glucosamine (O-GlcNAc) and oxidation.1 The potential interplay between PTMs of CRMPs likely contributes to a ‘PTM code’ that pairs a particular PTM signature with a particular function. As expression and/or PTMs of CRMPs are altered in mental (schizophrenia and mood disorders) and neurological (Alzheimer’s, prion encephalopathy, epilepsy and others) disorders,2 it is likely that targeting these PTM codes may be a novel therapeutic strategy for neuropsychiatric disorders. Here, we illustrate the potential of such targeting applied to a chronic pain model. Inhibiting CRMP2 interactions16 or phosphorylation17 has highlighted a central role for this protein in pain signaling transmission. Exactly how this is achieved is not known, but recent studies point to the regulation of voltage-gated ion channels by CRMP2 as a possible link.

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Author notes

  1. Current address: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Neuroscience Research Building, 320W 15th Street, Room 314, Indianapolis, IN 46202, USA.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA

    A Moutal, E T Dustrude, T M Largent-Milnes, T W Vanderah, M Khanna & R Khanna

  2. Department of Anesthesiology, College of Medicine, University of Arizona, Tucson, AZ, USA

    T W Vanderah & R Khanna

  3. Department of Neuroscience Graduate Interdisciplinary Program, College of Medicine, University of Arizona, Tucson, AZ, USA

    R Khanna

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  1. A Moutal
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Correspondence to R Khanna.

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Moutal, A., Dustrude, E.T., Largent-Milnes, T.M. et al. Blocking CRMP2 SUMOylation reverses neuropathic pain. Mol Psychiatry 23, 2119–2121 (2018). https://doi.org/10.1038/mp.2017.117

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