Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy, involve loss of muscle control resulting from death of motor neurons. Although the exact pathogenesis of these syndromes remains elusive, many are caused by genetically inherited mutations. Thus, it is v...
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Public Library of Science (PLoS)
2025-01-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1011547 |
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| author | Ying Zhang Lihong He Justin Gundelach Anjie Ge Helena Edlund Stefan Norlin Richard J Bram |
| author_facet | Ying Zhang Lihong He Justin Gundelach Anjie Ge Helena Edlund Stefan Norlin Richard J Bram |
| author_sort | Ying Zhang |
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| description | Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy, involve loss of muscle control resulting from death of motor neurons. Although the exact pathogenesis of these syndromes remains elusive, many are caused by genetically inherited mutations. Thus, it is valuable to identify additional genes that can impact motor neuron survival and function. In this report, we describe mice that express globally reduced levels of calcium-modulating cyclophilin ligand (CAML) protein. CAML is an essential component in the transmembrane domain recognition complex (TRC) pathway, responsible for inserting C-terminal tail anchored (TA) proteins into the endoplasmic reticulum membrane. The primary phenotype observed in these mice was rapid development of hind limb weakness and paralysis. Spinal cord sections revealed a loss of motor neuron cell bodies. Targeting CAML loss specifically to neurons using SLICK-H-Cre or synapsin-Cre transgenic mice yielded similar phenotypes, indicating that CAML plays a cell autonomous role in this process. We found that intracellular trafficking was perturbed in cells depleted of CAML, with aberrant release of procathepsin D and defective retention of CD222 within the trans-Golgi network, as well as reduced levels and mislocalization of syntaxin 5 (Stx5). Dysfunctional lysosomes and abnormal protein glycosylation were also revealed in CAML deficient cells, further indicating a defect in Golgi trafficking. In addition, we observed an identical phenotype in mice lacking ASNA1 in neurons, suggesting that CAML's role in sustaining muscle function is related to its involvement in the TRC pathway. Together, these findings implicate motor neuron survival as a key role for the TA protein insertion machinery in mice, which may shed light on the pathogenesis of neuromuscular disease in humans. |
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| id | doaj-art-08c2e2e5603847f892ed35e7d3523906 |
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| issn | 1553-7390 1553-7404 |
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| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj-art-08c2e2e5603847f892ed35e7d35239062025-08-20T02:00:55ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042025-01-01211e101154710.1371/journal.pgen.1011547Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.Ying ZhangLihong HeJustin GundelachAnjie GeHelena EdlundStefan NorlinRichard J BramMotor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy, involve loss of muscle control resulting from death of motor neurons. Although the exact pathogenesis of these syndromes remains elusive, many are caused by genetically inherited mutations. Thus, it is valuable to identify additional genes that can impact motor neuron survival and function. In this report, we describe mice that express globally reduced levels of calcium-modulating cyclophilin ligand (CAML) protein. CAML is an essential component in the transmembrane domain recognition complex (TRC) pathway, responsible for inserting C-terminal tail anchored (TA) proteins into the endoplasmic reticulum membrane. The primary phenotype observed in these mice was rapid development of hind limb weakness and paralysis. Spinal cord sections revealed a loss of motor neuron cell bodies. Targeting CAML loss specifically to neurons using SLICK-H-Cre or synapsin-Cre transgenic mice yielded similar phenotypes, indicating that CAML plays a cell autonomous role in this process. We found that intracellular trafficking was perturbed in cells depleted of CAML, with aberrant release of procathepsin D and defective retention of CD222 within the trans-Golgi network, as well as reduced levels and mislocalization of syntaxin 5 (Stx5). Dysfunctional lysosomes and abnormal protein glycosylation were also revealed in CAML deficient cells, further indicating a defect in Golgi trafficking. In addition, we observed an identical phenotype in mice lacking ASNA1 in neurons, suggesting that CAML's role in sustaining muscle function is related to its involvement in the TRC pathway. Together, these findings implicate motor neuron survival as a key role for the TA protein insertion machinery in mice, which may shed light on the pathogenesis of neuromuscular disease in humans.https://doi.org/10.1371/journal.pgen.1011547 |
| spellingShingle | Ying Zhang Lihong He Justin Gundelach Anjie Ge Helena Edlund Stefan Norlin Richard J Bram Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice. PLoS Genetics |
| title | Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice. |
| title_full | Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice. |
| title_fullStr | Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice. |
| title_full_unstemmed | Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice. |
| title_short | Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice. |
| title_sort | tail anchored protein insertion mediated by caml and trc40 links to neuromuscular function in mice |
| url | https://doi.org/10.1371/journal.pgen.1011547 |
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