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Article

Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration

1
Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
2
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(5), 4980; https://doi.org/10.3390/ijms24054980
Submission received: 16 January 2023 / Revised: 22 February 2023 / Accepted: 2 March 2023 / Published: 4 March 2023
(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

Abstract

All-trans-retinoic Acid (atRA) is the principal active metabolite of Vitamin A, essential for various biological processes. The activities of atRA are mediated by nuclear RA receptors (RARs) to alter gene expression (canonical activities) or by cellular retinoic acid binding protein 1 (CRABP1) to rapidly (minutes) modulate cytosolic kinase signaling, including calcium calmodulin-activated kinase 2 (CaMKII) (non-canonical activities). Clinically, atRA-like compounds have been extensively studied for therapeutic applications; however, RAR-mediated toxicity severely hindered the progress. It is highly desirable to identify CRABP1-binding ligands that lack RAR activity. Studies of CRABP1 knockout (CKO) mice revealed CRABP1 to be a new therapeutic target, especially for motor neuron (MN) degenerative diseases where CaMKII signaling in MN is critical. This study reports a P19-MN differentiation system, enabling studies of CRABP1 ligands in various stages of MN differentiation, and identifies a new CRABP1-binding ligand C32. Using the P19-MN differentiation system, the study establishes C32 and previously reported C4 as CRABP1 ligands that can modulate CaMKII activation in the P19-MN differentiation process. Further, in committed MN cells, elevating CRABP1 reduces excitotoxicity-triggered MN death, supporting a protective role for CRABP1 signaling in MN survival. C32 and C4 CRABP1 ligands were also protective against excitotoxicity-triggered MN death. The results provide insight into the potential of signaling pathway-selective, CRABP1-binding, atRA-like ligands in mitigating MN degenerative diseases.
Keywords: CRABP1; retinoic acid; ligand; CaMKII; non-canonical; neurodegeneration; motor neuron CRABP1; retinoic acid; ligand; CaMKII; non-canonical; neurodegeneration; motor neuron

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MDPI and ACS Style

Nhieu, J.; Milbauer, L.; Lerdall, T.; Najjar, F.; Wei, C.-W.; Ishida, R.; Ma, Y.; Kagechika, H.; Wei, L.-N. Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration. Int. J. Mol. Sci. 2023, 24, 4980. https://doi.org/10.3390/ijms24054980

AMA Style

Nhieu J, Milbauer L, Lerdall T, Najjar F, Wei C-W, Ishida R, Ma Y, Kagechika H, Wei L-N. Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration. International Journal of Molecular Sciences. 2023; 24(5):4980. https://doi.org/10.3390/ijms24054980

Chicago/Turabian Style

Nhieu, Jennifer, Liming Milbauer, Thomas Lerdall, Fatimah Najjar, Chin-Wen Wei, Ryosuke Ishida, Yue Ma, Hiroyuki Kagechika, and Li-Na Wei. 2023. "Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration" International Journal of Molecular Sciences 24, no. 5: 4980. https://doi.org/10.3390/ijms24054980

APA Style

Nhieu, J., Milbauer, L., Lerdall, T., Najjar, F., Wei, C.-W., Ishida, R., Ma, Y., Kagechika, H., & Wei, L.-N. (2023). Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration. International Journal of Molecular Sciences, 24(5), 4980. https://doi.org/10.3390/ijms24054980

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