Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration
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 ra...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/5/4980 |
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| author | Jennifer Nhieu Liming Milbauer Thomas Lerdall Fatimah Najjar Chin-Wen Wei Ryosuke Ishida Yue Ma Hiroyuki Kagechika Li-Na Wei |
| author_facet | Jennifer Nhieu Liming Milbauer Thomas Lerdall Fatimah Najjar Chin-Wen Wei Ryosuke Ishida Yue Ma Hiroyuki Kagechika Li-Na Wei |
| author_sort | Jennifer Nhieu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T07:21:16Z |
| format | Article |
| id | doaj.art-1c5eafed84d7427a82c374d23e4bfd80 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T07:21:16Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1c5eafed84d7427a82c374d23e4bfd802023-11-17T07:56:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01245498010.3390/ijms24054980Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron DegenerationJennifer Nhieu0Liming Milbauer1Thomas Lerdall2Fatimah Najjar3Chin-Wen Wei4Ryosuke Ishida5Yue Ma6Hiroyuki Kagechika7Li-Na Wei8Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USADepartment of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USADepartment of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USADepartment of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USADepartment of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USAInstitute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, JapanInstitute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, JapanInstitute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, JapanDepartment of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USAAll-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.https://www.mdpi.com/1422-0067/24/5/4980CRABP1retinoic acidligandCaMKIInon-canonicalneurodegeneration |
| spellingShingle | Jennifer Nhieu Liming Milbauer Thomas Lerdall Fatimah Najjar Chin-Wen Wei Ryosuke Ishida Yue Ma Hiroyuki Kagechika Li-Na Wei Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration International Journal of Molecular Sciences CRABP1 retinoic acid ligand CaMKII non-canonical neurodegeneration |
| title | Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration |
| title_full | Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration |
| title_fullStr | Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration |
| title_full_unstemmed | Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration |
| title_short | Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration |
| title_sort | targeting cellular retinoic acid binding protein 1 with retinoic acid like compounds to mitigate motor neuron degeneration |
| topic | CRABP1 retinoic acid ligand CaMKII non-canonical neurodegeneration |
| url | https://www.mdpi.com/1422-0067/24/5/4980 |
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