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. 2022 Aug;27(8):526-536.
doi: 10.1111/gtc.12971. Epub 2022 Jun 23.

Genetic inhibition of collapsin response mediator protein-2 phosphorylation ameliorates retinal ganglion cell death in normal-tension glaucoma models

Musukha Mala Brahma  1 , Kazuya Takahashi  1 , Kazuhiko Namekata  2 , Takayuki Harada  2 , Yoshio Goshima  3 , Toshio Ohshima  1   4
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Free article

Genetic inhibition of collapsin response mediator protein-2 phosphorylation ameliorates retinal ganglion cell death in normal-tension glaucoma models

Musukha Mala Brahma et al. Genes Cells. 2022 Aug.
Free article

Abstract

Glaucoma is a neurodegenerative disorder caused by the death of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is a cause of glaucoma. However, glaucoma often develops with normal IOP and is known as normal-tension glaucoma (NTG). Glutamate neurotoxicity is considered as one of the significant causes of NTG, resulting in excessive stimulation of retinal neurons via the N-methyl-D-aspartate (NMDA) receptors. The present study examined the phosphorylation of collapsin response mediator protein-2 (CRMP2), a protein that is abundantly expressed in neurons and involved in their development. In two mouse models, NMDA-injection and glutamate/aspartate transporter (GLAST) mutant, CRMP2 phosphorylation at the cyclin-dependent kinase-5 (Cdk5) site was elevated in RGCs. We confirmed that the decrease in the number of RGCs and thickness of the inner retinal layer (IRL) could be suppressed after NMDA administration in CRMP2KI/KI mice with genetically inhibited CRMP2 phosphorylation. Next, we investigated GLAST heterozygotes (GLAST+/-) with CRMP2KI/KI (GLAST+/-;CRMP2KI/KI) and GLAST knockout (GLAST-/-) mice with CRMP2KI/KI (GLAST-/-;CRMP2KI/KI) mice and compared them with GLAST+/- and GLAST-/- mice. pCRMP2 (S522) inhibition significantly reduced RGC loss and IRL thinning. These results suggest that the inhibition of CRMP2 phosphorylation could be a novel strategy for treating NTG.

Keywords: CRMP; GLAST; NMDA; inner retinal layer; mouse; normal tension glaucoma; phosphorylation; retinal ganglion cell.

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