{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T05:24:28Z","timestamp":1737177868652,"version":"3.33.0"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011547","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T20:12:05Z","timestamp":1737144725000},"page":"e1011547","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6742-5420","authenticated-orcid":true,"given":"Ying","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lihong","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Gundelach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3660-3642","authenticated-orcid":true,"given":"Anjie","family":"Ge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3553-7348","authenticated-orcid":true,"given":"Helena","family":"Edlund","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Norlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5940-6158","authenticated-orcid":true,"given":"Richard J.","family":"Bram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,1,17]]},"reference":[{"issue":"8389","key":"pgen.1011547.ref001","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/S0140-6736(84)92457-7","article-title":"The problems of neurons with long axons","volume":"1","author":"JB Cavanagh","year":"1984","journal-title":"Lancet"},{"issue":"3","key":"pgen.1011547.ref002","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0896-6273(00)81108-3","article-title":"From Charcot to SOD1: mechanisms of selective motor neuron death in ALS","volume":"24","author":"DW Cleveland","year":"1999","journal-title":"Neuron"},{"key":"pgen.1011547.ref003","article-title":"Syphilis\u2014lists of statistics pertinent to diagnosis","volume":"32","author":"S. 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