Collapsin response mediator protein family

Source: Wikipedia, the free encyclopedia.

Collapsin response mediator protein family or CRMP family consists of five intracellular

neuron degeneration after trauma induced injury.[3]

The modulation of CRMP-2 expression through various pharmaceuticals is a new and expanding area of research. By discovering chemicals that can either increase or decrease CRMP-2 expression, scientists can potentially reduce the effects of neurological diseases such as Alzheimer's disease and Parkinson's disease.[4][5]

History

Members of the CRMP family were discovered independently in different species by several groups working in parallel.

neurodegenerative disorders.[6]

Structure

Crystal structure of CRMP-1

CRMP1-5 are between 564 and 572

enzymes to allow them to bind metal atoms to their active site.[4]

Additionally, CRMPs can exist as homotetramers or as heterotetramers. The

kinases.[4]

Expression

The expression of CRMPs is regulated throughout development of the

GDNF, and FGF.[4]

In the adult

testis is detected only in the cell spermatid stage and CRMP-2 mRNA is found in lung tissue of the fetal mouse and adult human.[6]

The expression of CRMPs also can be found in the death or survival signaling of postmitotic neurons. Although CRMP is a cytosolic protein, significant amount of CRMP expression is detected as membrane associated at the leading edge of the growth cone lamellipodium and filopodia. Also, injury-induced CRMPs expression is found in sprouting fibers in both the central and peripheral nervous system.[4] CRMP-4 expression is promoted upon ischemic injury and is associated with neurons having intact morphology, suggesting that CRMP-4 provides a survival signal and may be involved in regeneration of neurons. Similarly, CRMP-2 has been suggested to participate in the survival and maintenance in postmitotic neurons as its over-expression accelerates nerve regeneration. However, CRMP-2 may also be involved in neuronal death as its expression is upregulated during the early stages of dopamine-induced neuronal apoptosis in cerebellar granule neurons.[7]

Mechanism, Function and Regulation

Axonal formation in developing neuron

CRMP-2 plays a role in neuronal

binding affinity to tubulin and Numb.[1]

Axonal growth cone guidance

In the

cytoskeletal reorganization of the growth cone and affect the growth cone motility.[2]

In

Sema3A, the interaction between CRMP tetramer and PlexA is blocked.[4] Phospholipase D2 (PLD-2) which is localized in the growth cone and is involved in actin cytoskeleton rearrangement, can be inhibited by CRMP-2 and its inhibition results in actin depolymerization and possibly affects axonal growth cone collapse. In the presence of CRMP-2, the signal can induce alterations of Rac-dependent pathway, which modulates the actin filament assembly in the growth cone.[6]

CRMP-2 is also involved in another growth cone collapse signal induced by extracellular

RhoA pathway, CRMP-1 interacts with Rho-kinase and modulates RhoA signaling. CRMP-2 can be regulated post-translationally by O-GluNAc (β-N-acetylglucosamine linked to hydroxyls of serine or threonine) as the modification blocks CRMP-2 from being phosphorylated.[6]

Trauma induced degeneration

Cleaved CRMP products play a considerable role in the degeneration of axons as a result of trauma inflicted on the central nervous system (CNS). As a result of trauma induced on the CNS, glutamate activates NMDA receptors leading to an influx of calcium that activates the calcium-dependent protease calpain. It has been shown that activated calpain proteolytically cleaves CRMP-3, creating a cleavage product of CRMP that interacts with vital cytosolic and nuclear molecules to bring about neurodegeneration.[7] The structure of this cleaved form of CRMP has not been determined yet, making it difficult to understand the protein-protein interactions that occur and why these forms are able to initiate neurodegeneration after CNS injury. Additionally, calpain inhibitors (ALLN) are shown to have prevented the CRMP‐3 cleavage and therefore no axonal degeneration or neuronal death, further suggesting that calpain targets CRMP-3 for cleavage during glutamate-induced neuronal death. Ca2+/calmodulin-dependent protein kinase II (CaMK II) is also activated by calcium influx through NMDA receptors, and is another possible activator of CRMP-3.[7] CRMP-3 is not the only CRMP involved in neuronal degeneration brought upon by trauma and cerebral ischemia, as all CRMPs are in fact targeted for cleavage to help promote degeneration.[7]

List of CRMPs (and associated knockout phenotypes and derived functions)

[9]

CRMP Phenotype in knockout mice Derived Function in cultured neurons
CRMP-1 Decrease in granule cell proliferation and apoptosis Sem3A-induced axonal guidance effect
Retarded neuronal migration
NT3
Disorientation of apical
dendrites
 Death of
neurons
Impaired dendritic spine density
Impaired LTP and spatial memory
CRMP-2 Severely abnormal dendritic patterning Axonal guidance by chemorepellent
Axon specification, elongation and branching
NT3
-induced axon outgrowth
Negative effect on axon extension induced by NGF
Accelerates axon regeneration of nerve-injured motor neurons
Neurotransmitter release
Resistance to glutamate toxicity through NR2B trafficking
Neuronal cell death
CRMP-3 Impaired dendritic spine maturation Neuronal cell death
Impaired LTP
Decrease of prepulse inhibition
CRMP-4 Increased proximal bifurcation phenotype in the CA1 hippocampus Axon elongation and branching
Inhibition of axon regeneration by myelin-derived inhibitors
Axonal degeneration and cell death
Sema3A-induced extension and branching of
dendrites
CRMP-5
Purkinje cells
 Filopodia and growth cone development
Impaired LTD Abrogation of the neurite outgrowth promotional activity of CRMP-2

Clinical significance

The expression of CRMPs is altered in

neurodegenerative diseases and these proteins likely play an essential role in the pathogenesis of disorders in the nervous system, including Alzheimer's disease, Parkinson's disease, schizophrenia, and many others. One pharmaceutical that is relatively effective in targeting CRMP-2 to reduce the results of a neurodegenerative disease is lacosamide. Lacosamide is used in combination with other types of medications to control various types of seizures, especially epilepsy. One of the ways lacosamide does this is by modulating CRMP-2, thus inducing neuroprotective effects and decreasing the epileptic effects in people with epilepsy.[10]

CRMP-2

GSK-3β.[12]

References

  1. ^
    PMID 14598368
    .
  2. ^
    PMID 11544032
    .
  3. PMID 22181040
    .
  4. ^
    PMID 17607942
    .
  5. PMID 32804096
    .
  6. ^
    S2CID 23916946
    .
  7. ^
    PMID 18544498. {{cite book}}: |journal= ignored (help
    )
  8. S2CID 22590453
    .
  9. S2CID 17567061
    .
  10. PMID 17199030
    .
  11. PMID 19519308
    .
  12. ^
    S2CID 37627165
    .
Retrieved from "https://en.wikipedia.org/w/index.php?title=Collapsin_response_mediator_protein_family&oldid=1189283019"