{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T20:09:11Z","timestamp":1782245351756,"version":"3.54.5"},"reference-count":77,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health, Italy, under the aegis of EU Joint Programme\u2014Neurodegenerative Disease Research (JPND)","award":["PATHWAYS-200-059"],"award-info":[{"award-number":["PATHWAYS-200-059"]}]},{"name":"Italian Ministry of Health, Italy","award":["Ricerca Corrente"],"award-info":[{"award-number":["Ricerca Corrente"]}]},{"DOI":"10.13039\/501100011878","name":"Flemish Government","doi-asserted-by":"publisher","award":["initiated Methusalem excellence program"],"award-info":[{"award-number":["initiated Methusalem excellence program"]}],"id":[{"id":"10.13039\/501100011878","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Flanders Impulse Program on Networks for Dementia Research","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"IWT and Belgian ALS liga","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer\u2019s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting\/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.<\/jats:p>","DOI":"10.3390\/ijms222413633","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T08:43:32Z","timestamp":1639989812000},"page":"13633","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer\u2019s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2836-8141","authenticated-orcid":false,"given":"Luisa","family":"Benussi","sequence":"first","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8292-6434","authenticated-orcid":false,"given":"Antonio","family":"Longobardi","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2055-6607","authenticated-orcid":false,"given":"Cemile","family":"Kocoglu","sequence":"additional","affiliation":[{"name":"Neurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, B-2610 Antwerp, Belgium"},{"name":"Department of 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Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Fostinelli","sequence":"additional","affiliation":[{"name":"MAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7727-0584","authenticated-orcid":false,"given":"Roberta","family":"Zanardini","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, I-25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcella","family":"Catania","sequence":"additional","affiliation":[{"name":"Neurology 5\/Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, I-20133 Milan, 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