Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

Abstract

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.

Cdk5‐mediated phosphorylation of CRMP‐2 enhances its interaction with CaV2.2

“…In addition to its canonical roles in neurite outgrowth, the web of interactions characterized now for CRMP-2 with motor proteins, kinases, channels, receptors, enzymes, and endocytosis-exocytosis related proteins suggests that CRMP-2 may serve as adaptors/ scaffold molecules and as traffic 'cops' [9]. Our laboratory has championed CRMP-2 as an important determinant of synaptic transmission [11][12][13]17,18].…”

“…Initially identified in chick sensory neurons as a protein responsible for growth cone retraction in response to negative guidance signals in the semaphorin 3A (Sema3A) pathway [1], CRMP-2 analogues were subsequently identified in Caenorhabditis elegans (uncoordinated protein-33 (Unc-33)) [2], in rodents ((named turned on after development 64 (TOAD-64)) in rats and Unc-33 like phosphoprotein (Ulip) in mice) [3][4][5], in humans (HUlip) [6,7] and in Drosophila Melanogaster [8]. Together with its established roles in neurite growth and retraction and kinesin-dependent axonal transport, mapping the CRMP-2 interactome has revealed previously unappreciated functions including affecting microtubule dynamics, protein endocytosis and vesicle recycling, as well as synaptic assembly (see reviews by Hensley [9] and Strittmatter [10]). …”

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

“…Hyperactive Cdk5-p25 hyperphosphorylates tau (also known as MAPT), which aggregates to form the neurofibrillary tangles observed in Alzheimer's disease. Furthermore, hyperphosphorylation of tau and CRMP2 (also known as DPYSL2) by Cdk5 also significantly impairs axonal transport, causing neuronal death (Hensley et al, 2011). Similarly, deregulation of Cdk5 by ectopic expression of p25 results in increased pausing of mitochondria in neurons (Morel et al, 2010).…”

Identification of a Proline-rich Inositol Polyphosphate 5-Phosphatase (PIPP)·Collapsin Response Mediator Protein 2 (CRMP2) Complex That Regulates Neurite Elongation

“…PIPP Regulates Axon Polarity and Neurite Length-CRMP2 promotes axon/dendrite selection, axon growth cone retraction, and axon elongation (18,19). We have previously shown that PIPP inhibits neurite extension (16), but have not examined its distribution or function in axons or dendrites.…”

“…Here we identify PIPP interacting partners as CRMP2 and tubulin by Y2H screening of brain libraries. CRMP2 is a neuronal adaptor protein that interacts with many binding partners, promoting axon polarity, neurite outgrowth, and elongation (18,19). PIPP and CRMP2 both independently bind ␤-tubulin and form a multiprotein complex with the motor protein, Kinesin-1.…”