{"doi":"10.1101/2023.08.08.552343","title":"The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in atrophic AMD","abstract":"Introductory paragraph Age-related macular degeneration (AMD), the leading cause of geriatric blindness, is a multi-factorial disease with retinal-pigmented epithelial (RPE) cell dysfunction as a central pathogenic driver. With RPE degeneration, lysosomal function is a core process that is disrupted. Transcription factors EB/E3 (TFEB/E3) tightly control lysosomal function; their disruption can cause aging disorders, such as AMD. Here, we show that induced pluripotent stem cells (iPSC)-derived RPE cells with the complement factor H variant [ CFH (Y402H)] have increased AKT2, which impairs TFEB/TFE3 nuclear translocation and lysosomal function. Increased AKT2 can inhibit PGC1α, which downregulates SIRT5, an AKT2 binding partner. SIRT5 and AKT2 co-regulate each other, thereby modulating TFEB-dependent lysosomal function in the RPE. Failure of the AKT2/SIRT5/TFEB pathway in the RPE induced abnormalities in the autophagy-lysosome cellular axis by upregulating secretory autophagy, thereby releasing a plethora of factors that likely contribute to drusen formation, a hallmark of AMD. Finally, overexpressing AKT2 in RPE cells in mice led to an AMD-like phenotype. Thus, targeting the AKT2/SIRT5/TFEB pathway could be a potential therapy for atrophic AMD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":394926,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":814384,"name":"Ruchi Sharma","orcid":"0000-0002-2219-5510","position":1,"is_corresponding":false},{"id":98999,"name":"Sridhar Bammidi","orcid":"0000-0002-3189-6140","position":2,"is_corresponding":false},{"id":1170270,"name":"Victoria Koontz","orcid":null,"position":3,"is_corresponding":false},{"id":1170271,"name":"Mihir Nemani","orcid":null,"position":4,"is_corresponding":false},{"id":746731,"name":"Meysam Yazdankhah","orcid":null,"position":5,"is_corresponding":false},{"id":266821,"name":"Katarzyna M. 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Samuel Zigler","orcid":null,"position":16,"is_corresponding":false},{"id":99002,"name":"Yuri V. Sergeev","orcid":"0000-0002-7204-6572","position":17,"is_corresponding":false},{"id":279286,"name":"Simon C. Watkins","orcid":"0000-0003-4092-1552","position":18,"is_corresponding":false},{"id":458697,"name":"Eric S. Goetzman","orcid":"0000-0001-9476-309X","position":19,"is_corresponding":false},{"id":99003,"name":"Miguel Flores‐Bellver","orcid":"0000-0003-3421-3699","position":20,"is_corresponding":false},{"id":1035815,"name":"Kai Kaarniranta","orcid":"0000-0003-2600-8679","position":21,"is_corresponding":false},{"id":250319,"name":"Akrit Sodhi","orcid":"0000-0001-5441-1014","position":22,"is_corresponding":false},{"id":277735,"name":"Kapil Bharti","orcid":"0000-0003-4884-3173","position":23,"is_corresponding":false},{"id":337908,"name":"James T. Handa","orcid":"0000-0003-1314-1745","position":24,"is_corresponding":false},{"id":99007,"name":"Debasish Sinha","orcid":"0000-0002-1739-5577","position":25,"is_corresponding":false},{"id":746225,"name":"Sayan Ghosh","orcid":"0000-0002-8722-2698","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T01:19:18.686170Z","pmid":"37609254","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":[]}