Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications
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Collapsin response mediator protein-2 (DPYSL2 or CRMP2) is a multifunctional adaptor protein within the central nervous system. In the developing brain or cell cultures, CRMP2 performs structural and regulatory functions related to cytoskeletal dynamics, vesicle trafficking and synaptic physiology whereas CRMP2 functions in adult brain are still being elucidated. CRMP2 has been associated with several neuropathologic or psychiatric conditions including Alzheimer’s disease (AD) and schizophrenia, either at the level of genetic polymorphisms; protein expression; post-translational modifications; or protein/protein interactions. In AD, CRMP2 is phosphorylated by glycogen synthase kinase-3β (GSK3β) and cyclin dependent protein kinase-5 (CDK5), the same kinases that act on tau protein in generating neurofibrillary tangles (NFTs). Phosphorylated CRMP2 collects in NFTs in association with the synaptic structure-regulating SRA1/WAVE1 (specifically Rac1-associated protein-1/WASP family verprolin-homologous protein-1) complex. This phenomenon could plausibly contribute to deficits in neural and synaptic structure that have been well documented in AD. This review discusses the essential biology of CRMP2 in the context of nascent data implicating CRMP2 perturbations as either a correlate of, or plausible contributor to, diverse neuropathologies. A discussion is made of recent findings that the atypical antidepressant tianeptine increases CRMP2 expression, whereas other, neuroactive small molecules including the epilepsy drug lacosamide and the natural brain metabolite lanthionine ketimine appear to bind CRMP2 directly with concomitant affects on neural structure. These findings constitute proofs-of-concept that pharmacological manipulation of CRMP2 is possible and hence, may offer new opportunities for therapy development against certain neurological diseases.
KeywordsCRMP2 Alzheimer Schizophrenia Epilepsy Lanthionine Tianeptine Lacosamide
This work was partially supported by a grant from the Judith and Jean Pape Adams Charitable Foundation (JJPAF). The authors thank Drs. Joseph Margiotta and Marthe Howard of the University of Toledo Medical Center for advice and guidance regarding DRG culture techniques. We thank Paula Kramer of the University of Toledo Medical Center for technical assistance in performing immunohistochemistry of AD brain specimens. We thank Professor Kozo Kaibuchi of the Nagoya University Graduate School of Medicine for his generous gift of antibodies against CRMP2 phospho-epitopes.
KH is an inventor on an issued US Patent no. 7,683,055 related to composition and use of lanthionine derivatives for treatment of inflammatory diseases.
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