Collapsin response mediator protein 3 deacetylates histone H4 to mediate nuclear condensation and neuronal death

Abstract

CRMP proteins play critical regulatory roles during semaphorin-mediated neurite outgrowth, neuronal differentiation and death. Albeit having a high degree of structure and sequence resemblance to that of liver dihydropyrimidinase, purified rodent brain CRMPs do not hydrolyze dihydropyrimidinase substrates. Here we found that mouse CRMP3 has robust histone H4 deacetylase activity. During excitotoxicity-induced mouse neuronal death, calpain-cleaved, N-terminally truncated CRMP3 undergoes nuclear translocation to cause nuclear condensation through deacetylation of histone H4. CRMP3-mediated deacetylation of H4 leads to de-repression of the E2F1 gene transcription and E2F1-dependent neuronal death. These studies revealed a novel mechanism of CRMP3 in neuronal death. Together with previous well established bodies of literature that inhibition of histone deacetylase activity provides neuroprotection, we envisage that inhibition of CRMP3 may represent a novel therapeutic approach towards excitotoxicity-induced neuronal death.

Mapping CRMP3 domains involved in dendrite morphogenesis and voltage-gated calcium channel regulation

“…CRMP3 expression was also found to be altered in Down syndrome (Weitzdoerfer et al, 2001). Recent studies revealed that CRMP3 has histone H4 deacetylase (HDAC) activity (Hou et al, 2013). Dendrites are one of the most plastic structures of the brain.…”

A beacon of hope in stroke therapy—Blockade of pathologically activated cellular events in excitotoxic neuronal death as potential neuroprotective strategies

“…CRMP3, a novel histone H4 deacetylase is cleaved by over-activated calpain in neurons undergoing excitotoxic neuronal death (Hou et al, 2013;Hou et al, 2006). Under physiological conditions, full-length CRMP3 does not exhibit histone H4 deacetylase activity…”

“…and resides in the cytosol. Upon cleavage by calpains at a site near the N-terminus, the truncated CRMP3 translocates into the nucleus where it exhibits robust histone H4 deacetylase activity, induces nuclear condensation and neuronal death (Hou et al, 2013).…”

Phaseic Acid, an Endogenous and Reversible Inhibitor of Glutamate Receptors in Mouse Brain

“…C57B/6 mice (20 -23 g) were obtained from Charles River and bred locally. Under temporary isofluorane anesthesia, MCAO was induced by the intraluminal insertion of a silicon-coated nylon filament (Re L910 PK5, Doccol Corporation) through the common carotid artery into the internal carotid artery and left in place for 60 min as we previously described (20)(21)(22)(23)(24)(25)(26). Cerebral blood flow (CBF) was monitored by laser Doppler flowmetry using a probe located in the ipsilateral parietal bone (1-2 mm posterior to bregma), and a >90% reduction in CSF was considered to indicate successful occlusion.…”

“…The analytes were ionized by negative-ion electrospray using the following conditions: capillary potential 1.75 kV; desolvation gas flow 1100 L/h; cone gas flow 150L/h; and source and desolvation gas temperatures at 120 Cortical neuronal cultures-Primary cortical neurons were prepared from embryonic E15-16 CD1 mice and cultured in neurobasal media supplemented with B-27 and N2 (Invitrogen Canada) for 7 -14 days as previously described (20,24,25). Neurons in these cultures are fully mature and are responsive to glutamate induced excitotoxicity.…”