{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T20:03:31Z","timestamp":1788897811040,"version":"build-2803163510"},"reference-count":79,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T00:00:00Z","timestamp":1758931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo de Investigaci\u00f3n Sanitaria, Instituto Salud Carlos III","award":["PI022\/00168"],"award-info":[{"award-number":["PI022\/00168"]}]},{"name":"Fondo de Investigaci\u00f3n Sanitaria, Instituto Salud Carlos III","award":["PI022\/00827"],"award-info":[{"award-number":["PI022\/00827"]}]},{"name":"AGAUR\/Generalitat de Catalunya and European Regional Development Fund","award":["SLT002\/16\/0030"],"award-info":[{"award-number":["SLT002\/16\/0030"]}]},{"name":"AGAUR\/Generalitat de Catalunya and European Regional Development Fund","award":["2021-SGR-01610"],"award-info":[{"award-number":["2021-SGR-01610"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite significant advances in understanding the genetics of Parkinson\u2019s disease (PD) and Parkinsonism, the diagnostic yield remains low. Pathogenic variants of GBA1, which encodes the lysosomal enzyme \u03b2-glucocerebrosidase and causes recessive Gaucher dis-ease, are recognized as the most important genetic risk factor for PD in heterozygous carriers. This study focuses on the functional genomics of rare genetic variations in other lysosomal hydrolytic enzymes genes in patient-derived fibroblasts. We examined 49 early-onset PD patients using whole exome sequencing and in silico panel analysis based on a curated PD gene list. Two patients were found to carry the p.Asp313Tyr variant in the X-linked GLA gene (encoding GALA, typically associated with Fabry disease), and one patient carried the p.Arg419Gln variant in GLB1 (encoding \u03b2-Gal, linked to the recessive GM1 gangliosidosis and mucopolysaccharidosis type IVB). The in silico study of both variants supports a potentially damaging impact on the encoded protein function and structural destabilization. Additional candidate variants were found related to lysosomes, Golgi apparatus and neurodegeneration, suggesting a multifactorial contribution to the disease. However, none of these variants met diagnostic standards. Functional assays showed a significant decrease in GALA expression and partial retention of the enzyme in the trans-Golgi network in fibroblasts with GLA:p.Asp313Tyr, while altered Golgi morphology was observed in fibroblasts with GLB1:p.Arg419Gln. Moreover, all patients exhibited abnormalities in lysosomal morphology, altered lysosomal pH, and impaired autophagic flux. Our findings suggest that rare, heterozygous variants in lysosomal-related genes, even when individually insufficient for monogenic disease, can converge to impair lysosomal homeostasis and autophagic flux in EOPD. The underlying genetic and cellular heterogeneity among patients emphasizes the importance of combining genetic and functional approaches to better understand the mechanisms behind the EOPD, which could enhance both diagnosis and future treatments.<\/jats:p>","DOI":"10.3390\/ijms26199454","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T10:54:48Z","timestamp":1759229688000},"page":"9454","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Lysosomal Network Defects in Early-Onset Parkinson\u2019s Disease Patients Carrying Rare Variants in Lysosomal Hydrolytic Enzyme Genes"],"prefix":"10.3390","volume":"26","author":[{"given":"Alba","family":"Pascual","sequence":"first","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3349-9517","authenticated-orcid":false,"given":"Thaleia","family":"Moulka","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriol","family":"de F\u00e0bregues","sequence":"additional","affiliation":[{"name":"Neurodegenerative Diseases Research Group, Vall d\u2019Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), 08035 Barcelona, Spain"},{"name":"Movement Disorders Unit, Neurology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8604-6778","authenticated-orcid":false,"given":"Roberta","family":"Repossi","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro J.","family":"Garc\u00eda-Ruiz","sequence":"additional","affiliation":[{"name":"Unit of Movement Disorders, Department of Neurology, Fundaci\u00f3n Jimenez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1098-3376","authenticated-orcid":false,"given":"Saida","family":"Ortolano","sequence":"additional","affiliation":[{"name":"Rare Diseases & Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Servicio Gallego de Salud-Universidad de Vigo (SERGAS-UVIGO), 36213 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-2955","authenticated-orcid":false,"given":"Marisel","family":"De Lucca","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Health Sciences, Universidad T\u00e9cnica de Manab\u00ed, Portoviejo 130105, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Vela-Desojo","sequence":"additional","affiliation":[{"name":"Movement Disorders Unit, Department of Neurology, Hospital Universitario Fundaci\u00f3n Alcorc\u00f3n, 28922 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9244-6513","authenticated-orcid":false,"given":"Marta","family":"Alves-Villar","sequence":"additional","affiliation":[{"name":"Rare Diseases & Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Servicio Gallego de Salud-Universidad de Vigo (SERGAS-UVIGO), 36213 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Fr\u00edas","sequence":"additional","affiliation":[{"name":"Confocal Microscopy and Cellular Imaging Unit, Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cici","family":"Feliz-Feliz","sequence":"additional","affiliation":[{"name":"Unit of Movement Disorders, Department of Neurology, Fundaci\u00f3n Jimenez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9530-6234","authenticated-orcid":false,"given":"M\u00f2nica","family":"Rold\u00e1n","sequence":"additional","affiliation":[{"name":"Confocal Microscopy and Cellular Imaging Unit, Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"},{"name":"Department of Genetics, Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Olival","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guerau","family":"Fern\u00e0ndez","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de D\u00e9u, 08950 Barcelona, Spain"},{"name":"Department of Genetics, Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8635-5421","authenticated-orcid":false,"given":"Francesc","family":"Palau","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de D\u00e9u, 08950 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"},{"name":"Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"},{"name":"Division of Pediatrics, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0350-6376","authenticated-orcid":false,"given":"Jordi","family":"Pijuan","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de D\u00e9u, 08950 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6790-6988","authenticated-orcid":false,"given":"Janet","family":"Hoenicka","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine, Center for Genomic Sciences in Medicine, Institut de Recerca Sant Joan de D\u00e9u, 08950 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S1474-4422(19)30287-X","article-title":"The Genetic Architecture of Parkinson\u2019s Disease","volume":"19","author":"Blauwendraat","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4996","DOI":"10.1093\/hmg\/dds335","article-title":"Using Genome-Wide Complex Trait Analysis to Quantify \u201cmissing Heritability\u201d in Parkinson\u2019s Disease","volume":"21","author":"Keller","year":"2012","journal-title":"Hum. 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