{"doi":"10.1016/j.ibneur.2025.06.005","title":"Downregulation of AKT-mediated p27Kip1 phosphorylation with shift to sphingomyelin synthesis in CLN3 disease","abstract":"CLN3 disease is a fatal childhood neurodegenerative disorder without drug-modifying therapies. Wild-type CLN3 gene is anti-apoptotic. Previous work proves that CLN3 disease pathogenesis is associated with reduced cell viability/apoptotic cell death and increase in ceramide, in cells and brains of patients and in Cln3 Δex7/8 mouse brain. AKT, a serine/threonine protein kinase, is at the core of a complex signaling pathway regulating apoptosis and cell proliferation and is neuroprotective. AKT fulfils this function via cyclin-dependent kinase inhibitor p27 Kip1 phosphorylation at residue T198 resulting in its cytoplasmic localization and promotion of cell survival. Transcriptomic analysis of gene expression using microarrays, validation by Western blot and real-time PCR, demonstrate that AKT is downregulated in CLN3-deficient cells and Cln3 Δex7/8 mouse brain. Conversely, CLN3 overexpression causes upregulation of AKT proteins. Novel data shows that CLN3 deficiency reduces AKT-mediated p27 Kip1 T198 phosphorylation, possibly leading to reduced cell viability. Dysregulation in AKT/p27 Kip1 signaling alters sphingolipid metabolism. Results confirm an increase in sphingomyelin synthesis in CLN3-deficient cells.","journal":"IBRO Neuroscience Reports","year":2025,"id":541606,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"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":1429884,"name":"Jihane Soueid","orcid":"0000-0002-1973-8705","position":1,"is_corresponding":false},{"id":1430325,"name":"Sara Saab","orcid":null,"position":2,"is_corresponding":false},{"id":1429885,"name":"Nadine J. Makhoul","orcid":"0009-0006-6870-2262","position":3,"is_corresponding":false},{"id":1429886,"name":"Zeinab Hamzé","orcid":"0000-0002-3753-1038","position":4,"is_corresponding":false},{"id":1430326,"name":"Lara El-Bazzal","orcid":null,"position":5,"is_corresponding":false},{"id":1430327,"name":"Joelle Makoukji","orcid":null,"position":6,"is_corresponding":false},{"id":1038210,"name":"Rose‐Mary Boustany","orcid":"0000-0002-2066-0079","position":7,"is_corresponding":false},{"id":1430324,"name":"Fatima Bilal","orcid":null,"position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T02:52:47.161928Z","pmid":"40678187","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":[]}