{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:06:00Z","timestamp":1790899560776,"version":"4.1.0"},"reference-count":65,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T00:00:00Z","timestamp":1654300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Regione Toscana","award":["SG-2018-12367839"],"award-info":[{"award-number":["SG-2018-12367839"]}]},{"name":"Regione Toscana","award":["GGP20011"],"award-info":[{"award-number":["GGP20011"]}]},{"name":"Italian Ministry of Health","award":["SG-2018-12367839"],"award-info":[{"award-number":["SG-2018-12367839"]}]},{"name":"Italian Ministry of Health","award":["GGP20011"],"award-info":[{"award-number":["GGP20011"]}]},{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"publisher","award":["SG-2018-12367839"],"award-info":[{"award-number":["SG-2018-12367839"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"publisher","award":["GGP20011"],"award-info":[{"award-number":["GGP20011"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach, followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5\u2212\/\u2212 mice, to unravel affected pathways and modifying factors involved in this disease scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments.<\/jats:p>","DOI":"10.3390\/cells11111840","type":"journal-article","created":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T09:42:32Z","timestamp":1654335752000},"page":"1840","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5534-8253","authenticated-orcid":false,"given":"Stefano","family":"Doccini","sequence":"first","affiliation":[{"name":"Molecular Medicine\u2013IRCCS Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0194-0702","authenticated-orcid":false,"given":"Maria","family":"Marchese","sequence":"additional","affiliation":[{"name":"Molecular Medicine\u2013IRCCS Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4903-6878","authenticated-orcid":false,"given":"Federica","family":"Morani","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9138-506X","authenticated-orcid":false,"given":"Nicola","family":"Gammaldi","sequence":"additional","affiliation":[{"name":"Molecular Medicine\u2013IRCCS Stella Maris, 56128 Pisa, Italy"},{"name":"Ph.D. Program in Neuroscience, University of Florence, 50121 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Mero","sequence":"additional","affiliation":[{"name":"Molecular Medicine\u2013IRCCS Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1590-4558","authenticated-orcid":false,"given":"Francesco","family":"Pezzini","sequence":"additional","affiliation":[{"name":"Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37129 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0184-3352","authenticated-orcid":false,"given":"Rabah","family":"Soliymani","sequence":"additional","affiliation":[{"name":"HiLIFE, Meilahti Clinical Proteomics Core Facility, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9374-883X","authenticated-orcid":false,"given":"Melissa","family":"Santi","sequence":"additional","affiliation":[{"name":"NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR, 56127 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0067-2240","authenticated-orcid":false,"given":"Giovanni","family":"Signore","sequence":"additional","affiliation":[{"name":"Fondazione Pisana per la Scienza, 56017 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asahi","family":"Ogi","sequence":"additional","affiliation":[{"name":"Molecular Medicine\u2013IRCCS Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3831-4200","authenticated-orcid":false,"given":"Silvia","family":"Rocchiccioli","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology-CNR, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6717-8589","authenticated-orcid":false,"given":"Katja M.","family":"Kanninen","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Simonati","sequence":"additional","affiliation":[{"name":"Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37129 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3683-4096","authenticated-orcid":false,"given":"Maciej M.","family":"Lalowski","sequence":"additional","affiliation":[{"name":"HiLIFE, Meilahti Clinical Proteomics Core Facility, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland"},{"name":"Institute of Bioorganic Chemistry, PAS, Department of Biomedical Proteomics, 61-704 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1359-9062","authenticated-orcid":false,"given":"Filippo M.","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Molecular Medicine\u2013IRCCS Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,4]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"NCL Disorders: Frequent Causes of Childhood Dementia","volume":"7","author":"Schulz","year":"2013","journal-title":"Iran. 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