Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degeneration
Abstract Sterile alpha and Toll/interleukin-1 receptor motif containing 1 (SARM1), a nicotinamide adenine dinucleotide (NAD)-utilizing enzyme, mediates axon degeneration (AxD) in various neurodegenerative diseases. It is activated by nicotinamide mononucleotide (NMN) to produce a calcium messenger,...
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07342-4 |
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| author | Wen Jie Zhu Jun Liu Wan Hua Li Zhi Ying Zhao Chongquan Huang Jian Yuan Yang Hon Cheung Lee Yong Juan Zhao |
| author_facet | Wen Jie Zhu Jun Liu Wan Hua Li Zhi Ying Zhao Chongquan Huang Jian Yuan Yang Hon Cheung Lee Yong Juan Zhao |
| author_sort | Wen Jie Zhu |
| collection | DOAJ |
| description | Abstract Sterile alpha and Toll/interleukin-1 receptor motif containing 1 (SARM1), a nicotinamide adenine dinucleotide (NAD)-utilizing enzyme, mediates axon degeneration (AxD) in various neurodegenerative diseases. It is activated by nicotinamide mononucleotide (NMN) to produce a calcium messenger, cyclic ADP-ribose (cADPR). This activity is blocked by elevated NAD level. Here, we verified this metabolic regulation in somatic HEK-293T cells by overexpressing NMN-adenyltransferase to elevate cellular NAD, which resulted not only in inhibition of their own SARM1 from producing cADPR but, surprisingly, also in the 5–10 neighboring wildtype cells in mixed cultures via connexin (Cx)-43. Direct visualization of gap junction intercellular communication (GJIC) was achieved by incubating cells with a permeant probe, PC11, which is converted by SARM1 into PAD11, a fluorescent NAD analog capable of traversing GJs. Extending the findings to dorsal root ganglion neurons, we further showed that CZ-48, a permeant NMN analog, or axotomy, activated SARM1 and the produced PAD11 was transferred to contacting axons via GJIC. The gap junction involved was identified as Cx36 instead. This neuronal GJIC was demonstrated to be functional, enabling healthy neurons to protect adjacent axotomized axons from degeneration. Inhibition of GJIC in mice by AAV-PHP.eB-mediated knockdown of Cx36 in brain induced neuroinflammation, which in turn activated SARM1 and resulted in axon degeneration as well as behavioral deficits. Our results demonstrate a novel intercellular regulation mechanism of SARM1 and reveal a protective role of healthy tissue against AxD induced by injury or neuroinflammation. |
| format | Article |
| id | doaj-art-ef44ecec6d5e453d8d294041f0eb6938 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-ef44ecec6d5e453d8d294041f0eb69382025-01-19T12:40:49ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111110.1038/s41419-025-07342-4Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degenerationWen Jie Zhu0Jun Liu1Wan Hua Li2Zhi Ying Zhao3Chongquan Huang4Jian Yuan Yang5Hon Cheung Lee6Yong Juan Zhao7State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate SchoolState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate SchoolState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate SchoolState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate SchoolState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate SchoolCiechanover Institute of Precision and Regenerative Medicine, School of Life and Health Sciences, School of Medicine, The Chinese University of Hong KongState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate SchoolState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate SchoolAbstract Sterile alpha and Toll/interleukin-1 receptor motif containing 1 (SARM1), a nicotinamide adenine dinucleotide (NAD)-utilizing enzyme, mediates axon degeneration (AxD) in various neurodegenerative diseases. It is activated by nicotinamide mononucleotide (NMN) to produce a calcium messenger, cyclic ADP-ribose (cADPR). This activity is blocked by elevated NAD level. Here, we verified this metabolic regulation in somatic HEK-293T cells by overexpressing NMN-adenyltransferase to elevate cellular NAD, which resulted not only in inhibition of their own SARM1 from producing cADPR but, surprisingly, also in the 5–10 neighboring wildtype cells in mixed cultures via connexin (Cx)-43. Direct visualization of gap junction intercellular communication (GJIC) was achieved by incubating cells with a permeant probe, PC11, which is converted by SARM1 into PAD11, a fluorescent NAD analog capable of traversing GJs. Extending the findings to dorsal root ganglion neurons, we further showed that CZ-48, a permeant NMN analog, or axotomy, activated SARM1 and the produced PAD11 was transferred to contacting axons via GJIC. The gap junction involved was identified as Cx36 instead. This neuronal GJIC was demonstrated to be functional, enabling healthy neurons to protect adjacent axotomized axons from degeneration. Inhibition of GJIC in mice by AAV-PHP.eB-mediated knockdown of Cx36 in brain induced neuroinflammation, which in turn activated SARM1 and resulted in axon degeneration as well as behavioral deficits. Our results demonstrate a novel intercellular regulation mechanism of SARM1 and reveal a protective role of healthy tissue against AxD induced by injury or neuroinflammation.https://doi.org/10.1038/s41419-025-07342-4 |
| spellingShingle | Wen Jie Zhu Jun Liu Wan Hua Li Zhi Ying Zhao Chongquan Huang Jian Yuan Yang Hon Cheung Lee Yong Juan Zhao Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degeneration Cell Death and Disease |
| title | Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degeneration |
| title_full | Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degeneration |
| title_fullStr | Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degeneration |
| title_full_unstemmed | Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degeneration |
| title_short | Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degeneration |
| title_sort | gap junction intercellular communications regulates activation of sarm1 and protects against axonal degeneration |
| url | https://doi.org/10.1038/s41419-025-07342-4 |
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