{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE299nnn/GSE299278/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299278"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Encephalopathy-linked UFM1 variants impede neuronal protein translation, development and function","description":"Genetic variants that hinder post-translational protein modifications by UFM1, UFMylation, cause encephalopathies. UFMylation regulates endoplasmic reticulum (ER) homeostasis, but how UFMylation-deficiencies cause selective neurological defects is unknown. Using Ufm1 knock-out mice, we investigated two types of UFMylation pathologies, UFM1 loss and expression of a pathogenic UFM1-R81C variant. We found that UFM1-deficiency confounds neuron development and synapse function. Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the PERK-UPR pathway, and reduced protein translation. These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C. UFM1-deficient and UFM1-R81Cexpressing neurons display distinct responses to ER stress, indicating that UFM1-R81C is not merely a loss-of-function variant. Exploring therapeutic options, we show that the PERK-UPR inhibitor Trazodone restores protein translation solely in UFM1-R81C-expressing neurons, and increases synapse number. Our study unveils a pivotal role for UFMylation in neuronal development, provides a molecular understanding of the signaling mechanisms altered in UFM1- associated encephalopathies, and offers important insights into potential treatments for these Genetic variants that hinder post-translational protein modifications by UFM1, UFMylation, cause encephalopathies. UFMylation regulates endoplasmic reticulum (ER) homeostasis, but how UFMylation-deficiencies cause selective neurological defects is unknown. Using Ufm1 knock-out mice, we investigated two types of UFMylation pathologies, UFM1 loss and expression of a pathogenic UFM1-R81C variant. We found that UFM1-deficiency confounds neuron development and synapse function. Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the PERK-UPR pathway, and reduced protein translation. These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C. UFM1-deficient and UFM1-R81C-expressing neurons display distinct responses to ER stress, indicating that UFM1-R81C is not merely a loss-of-function variant. Exploring therapeutic options, we show that the PERK-UPR inhibitor Trazodone restores protein translation solely in UFM1-R81C-expressing neurons, initiating an increase in synapse number. Our study unveils a pivotal role for UFMylation in neuronal development and provides a molecular understanding of the signaling mechanisms altered in UFM1-associated encephalopathies, offering valuable insights into potential treatments for these disorders.","dates":{"publication":"2026/04/22"},"accession":"GSE299278","cross_references":{"GSM":["GSM9036557","GSM9036546","GSM9036558","GSM9036547","GSM9036559","GSM9036548","GSM9036549","GSM9036553","GSM9036543","GSM9036554","GSM9036555","GSM9036544","GSM9036556","GSM9036545","GSM9036560","GSM9036550","GSM9036551","GSM9036552"],"GPL":["24247"],"GSE":["299278"],"taxon":["Mus musculus"],"PMID":["[41731076]"]}}