Opening Pandora‘s Jar: A Primer on the Putative Roles of Crmp2 In A Panoply of Neurodegenerative, Sensory and Motor Neuron, and Central Disorders

Abstract

CRMP2, also known as DPYSL2/DRP2, Unc-33, Ulip or TUC2, is a cytosolic phosphoprotein that mediates axon/dendrite specification and axonal growth. Mapping the CRMP2 interactome has revealed previously unappreciated functions subserved by this protein. Together with its canonical roles in neurite growth and retraction and kinesin-dependent axonal transport, it is now known that CRMP2 interacts with numerous binding partners to affect microtubule dynamics; protein endocytosis and vesicular cycling, synaptic assembly, calcium channel regulation and neurotransmitter release. CRMP2 signaling is regulated by post-translational modifications, including glycosylation, oxidation, proteolysis and phosphorylation; the latter being a fulcrum of CRMP2 functions. Here, the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders are discussed and evidence is presented for therapeutic strategies targeting CRMP2 functions.

Keywords:

• Alzheimer‘s disease
• amyotrophic lateral sclerosis
• axon elongation
• CRMP2
• CRMP2/CLN6/KLC4 signaling complex
• CRMP2 hyperphosphorylation
• excitotoxicity
• multiple sclerosis
• neuropathic pain
• oxidative damage

Acknowledgements

We apologize to some of our CRMP2 colleagues for not being able to cite their work due to space restrictions.

Financial & competing interests disclosure

This work in our laboratories was supported, in part, by grants from the Indiana Clinical and Translational Sciences Institute funded, in part, by a Project Development Team Grant Number (RR025761) from the NIH, National Center for Research Resources, Clinical and Translational Sciences Award, and the Indiana State Department of Health – Spinal Cord and Brain Injury Fund (A70–9–079138 to R Khanna). It was also funded by the NIH (R21-NSO66279, RO1-AG 031553 to K Hensley, AG-05119 to A Butterfield ), the Muscular Dystrophy Association (MDA217526 to K Hensley), a Neuronal Ceroid Lipofuscinosis Foundation award (to J Weimer), a National Scientist Development grant from the American Heart Association (SDG5280023 to R Khanna), a Neurofibromatosis New Investigator Award from the Department of Defense Congressionally Directed Military Medical Research and Development Program (NF1000099 to R Khanna), the Indiana University Biomedical Committee – Research Support Funds (2286501 to R Khanna), a Showalter Trust Foundation award (to R Khanna), a Research Inventions and Scientific Commercialization grant (to R Khanna) and a Funding Opportunities for Research Commercialization and Economic Success grant initiative from the Indiana CTSI (to R Khanna), and the Elwert Award in Medicine (to R Khanna). R Khanna is a shareholder of Sophia Therapeutics LLC. JM Brittain is the recipient of a Larry Kays Medical Neuroscience Fellowship and the Jack and Linda Gill Doctoral Thesis Award. SM Wilson is a Stark Scholar. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work in our laboratories was supported, in part, by grants from the Indiana Clinical and Translational Sciences Institute funded, in part, by a Project Development Team Grant Number (RR025761) from the NIH, National Center for Research Resources, Clinical and Translational Sciences Award, and the Indiana State Department of Health – Spinal Cord and Brain Injury Fund (A70–9–079138 to R Khanna). It was also funded by the NIH (R21-NSO66279, RO1-AG 031553 to K Hensley, AG-05119 to A Butterfield ), the Muscular Dystrophy Association (MDA217526 to K Hensley), a Neuronal Ceroid Lipofuscinosis Foundation award (to J Weimer), a National Scientist Development grant from the American Heart Association (SDG5280023 to R Khanna), a Neurofibromatosis New Investigator Award from the Department of Defense Congressionally Directed Military Medical Research and Development Program (NF1000099 to R Khanna), the Indiana University Biomedical Committee – Research Support Funds (2286501 to R Khanna), a Showalter Trust Foundation award (to R Khanna), a Research Inventions and Scientific Commercialization grant (to R Khanna) and a Funding Opportunities for Research Commercialization and Economic Success grant initiative from the Indiana CTSI (to R Khanna), and the Elwert Award in Medicine (to R Khanna). R Khanna is a shareholder of Sophia Therapeutics LLC. JM Brittain is the recipient of a Larry Kays Medical Neuroscience Fellowship and the Jack and Linda Gill Doctoral Thesis Award. SM Wilson is a Stark Scholar. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.