{"doi":"10.1016/j.nbd.2025.106890","title":"Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease model","abstract":"Lysosomal storage disorders (LSDs) represent 70 inherited metabolic diseases, in most of which neurodegeneration is a devastating manifestation. The CLN1 disease is a fatal neurodegenerative LSD, caused by inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1). S-palmitoylation, a reversable posttranslational modification by saturated fatty acids (generally palmitate) facilitates endosomal trafficking of many proteins, especially in the brain. While palmitoyl-acyltransferases (called ZDHHCs) catalyze S-palmitoylation, depalmitoylation is mediated by palmitoyl-protein thioesterases (PPTs). We previously reported that in Cln1 −/− mice, which mimic human CLN1-disease, endoplasmic reticulum (ER)-stress leads to unfolded protein response (UPR) contributing to neurodegeneration. However, the mechanism underlying ER-stress has remained elusive. The anterograde (ER to Golgi) protein-trafficking is mediated via COPII (coat protein complex II) vesicles, whereas the retrograde transport (Golgi to ER) is mediated by COPI vesicles. We hypothesized that dysregulated anterograde protein-trafficking causing stagnation of proteins in the ER leads to ER-stress in Cln1 −/− mice. We found that the levels of five COPII vesicle-associated proteins (i.e. Sar1, Sec23, Sec24, Sec13 and Sec31) are significantly higher in the ER-fractions of cortical tissues from Cln1 −/− mice compared with those from their WT littermates. Remarkably, all COPII proteins, except Sec13, undergo S-palmitoylation. Moreover, CLN8, a Batten disease-protein, requires dynamic S-palmitoylation (palmitoylation-depalmitoylation) for ER-Golgi trafficking. Intriguingly, Ppt1-deficiency in Cln1 −/− mice impairs ER-Golgi trafficking of Cln8-protein along with several other COPII-associated proteins. We propose that impaired anterograde trafficking causes excessive accumulation of proteins in the ER causing ER-stress and UPR contributing to neurodegeneration in CLN1 disease. • CLN1 disease is a fatal neurodegenerative lysosomal storage disorder. • In CLN1-disease, endoplasmic reticulum stress contributes to neurodegeneration. • However, the mechanism underlying ER-stress has remained elusive. • In Cln1 −/− mice, Ppt1-deficiency impairs anterograde (ER to Golgi) trafficking of proteins. • Impaired protein trafficking causing stagnation of proteins in the ER mediates ER-stress.","journal":"Neurobiology of Disease","year":2025,"id":520835,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":366099,"name":"Abhilash P. Appu","orcid":"0000-0001-6805-5540","position":1,"is_corresponding":false},{"id":1390719,"name":"K. Gopal","orcid":"0000-0002-0329-8442","position":2,"is_corresponding":false},{"id":366101,"name":"Avisek Mondal","orcid":"0000-0003-1443-219X","position":3,"is_corresponding":false},{"id":748417,"name":"Neil D. Perkins","orcid":"0000-0002-9756-3656","position":4,"is_corresponding":false},{"id":366103,"name":"Anil B. Mukherjee","orcid":"0000-0003-4445-5464","position":5,"is_corresponding":false},{"id":1279416,"name":"Nisha Plavelil","orcid":null,"position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T02:49:32.958846Z","pmid":"40158736","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}