{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T21:19:20Z","timestamp":1773868760282,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Aims: Tay\u2013Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by \u03b2-hexosaminidase A (HexA) leads to the accumulation of GM2 ganglioside in neuronal lysosomes. Despite the storage phenotype, the role of autophagy and its regulation by mTOR has yet to be explored in the neuropathogenesis. Accordingly, we investigated the effects on autophagy and lysosomal integrity using skin fibroblasts obtained from patients with Tay\u2013Sachs and Sandhoff diseases. Results: Pathological autophagosomes with impaired autophagic flux, an abnormality confirmed by electron microscopy and biochemical studies revealing the accelerated release of mature cathepsins and HexA into the cytosol, indicating increased lysosomal permeability. GM2 fibroblasts showed diminished mTOR signalling with reduced basal mTOR activity. Accordingly, provision of a positive nutrient signal by L-arginine supplementation partially restored mTOR activity and ameliorated the cytopathological abnormalities. Innovation: Our data provide a novel molecular mechanism underlying GM2 gangliosidosis. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for these diseases. Conclusions: We contend that the expression of autophagy\/lysosome\/mTOR-associated molecules may prove useful peripheral biomarkers for facile monitoring of treatment of GM2 gangliosidosis and neurodegenerative disorders that affect the lysosomal function and disrupt autophagy.<\/jats:p>","DOI":"10.3390\/cells10113122","type":"journal-article","created":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T23:02:41Z","timestamp":1636671761000},"page":"3122","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation"],"prefix":"10.3390","volume":"10","author":[{"given":"Beatriz","family":"Castej\u00f3n-Vega","sequence":"first","affiliation":[{"name":"Research Laboratory, Oral Medicine Department, University of Sevilla, 41009 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6736-6141","authenticated-orcid":false,"given":"Alejandro","family":"Rubio","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biologia del Desarrollo (CABD, UPO-CSIC-JA), Facultad de Ciencias Experimentales (\u00c1rea de Gen\u00e9tica), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio J.","family":"P\u00e9rez-Pulido","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biologia del Desarrollo (CABD, UPO-CSIC-JA), Facultad de Ciencias Experimentales (\u00c1rea de Gen\u00e9tica), Universidad Pablo de Olavide, 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9048-9086","authenticated-orcid":false,"given":"Jos\u00e9 L.","family":"Quiles","sequence":"additional","affiliation":[{"name":"Department of Physiology, Institute of Nutrition and Food Technology \u201cJos\u00e9 Mataix Verd\u00fa\u201d, Biomedical Research Center, University of Granada, 18071 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon D.","family":"Lane","sequence":"additional","affiliation":[{"name":"Cell Biology Laboratories, School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz","family":"Fern\u00e1ndez-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Acci\u00f3n y Cura Para Tay-Sachs (ACTAYS), 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Bego\u00f1a","family":"Cach\u00f3n-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3361-6974","authenticated-orcid":false,"given":"Carmen","family":"Mart\u00edn-Ruiz","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Newcastle University, Newcastle upon Tyne NE4 5 PL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Sanz","sequence":"additional","affiliation":[{"name":"Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4951-9941","authenticated-orcid":false,"given":"Timothy M.","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"El\u00edsabet","family":"Alcocer-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Departamento de Psicolog\u00eda Experimental, Facultad de Psicolog\u00eda, Universidad de Sevilla, 41009 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0151-3644","authenticated-orcid":false,"given":"Mario D.","family":"Cordero","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n e Innovaci\u00f3n en Ciencias Biom\u00e9dicas de C\u00e1diz (INiBICA), 11009 Cadiz, Spain"},{"name":"CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/cr.2013.161","article-title":"Autophagy and human diseases","volume":"24","author":"Jiang","year":"2014","journal-title":"Cell Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s13023-016-0544-6","article-title":"Aspartylglycosaminuria: A review","volume":"11","author":"Arvio","year":"2016","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1080\/15548627.2015.1106668","article-title":"MTOR, PIK3C3, and autophagy: Signaling the beginning from the end","volume":"11","author":"Munson","year":"2015","journal-title":"Autophagy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1016\/j.celrep.2013.10.042","article-title":"Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease","volume":"5","author":"Sarkar","year":"2013","journal-title":"Cell Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"353","DOI":"10.15252\/emmm.201606547","article-title":"Modulation of mTOR signaling as a strategy for the treatment of Pompe disease","volume":"9","author":"Lim","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"68","DOI":"10.2174\/1566523218666180404162622","article-title":"Genetics and Therapies for GM2 Gangliosidosis","volume":"18","author":"Zaccariotto","year":"2018","journal-title":"Curr. Gene Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1038\/emboj.2012.32","article-title":"A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB","volume":"31","author":"Settembre","year":"2012","journal-title":"EMBO J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/humu.20654","article-title":"Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker","volume":"29","author":"Wildeman","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13478","DOI":"10.1074\/jbc.M308523200","article-title":"Pharmacological enhancement of b-hexosaminidase activity in fibroblasts from adult Tay-Sachs and Sandhoff Patients","volume":"279","author":"Tropak","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/emmm.201202176","article-title":"Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease","volume":"5","author":"Spampanato","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1242\/jcs.146365","article-title":"TFEB at a glance","volume":"129","author":"Napolitano","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_12","first-page":"214","article-title":"Bcl-2: Beclin 1 complex: Multiple, mechanisms regulating autophagy\/apoptosis toggle switch","volume":"2","author":"Marquez","year":"2012","journal-title":"Am. J. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.15252\/embr.201744069","article-title":"Rab7b modulates autophagic flux by interacting with Atg4B","volume":"18","author":"Kjos","year":"2017","journal-title":"EMBO Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1093\/hmg\/ddu603","article-title":"Ataxia is the major neuropathological finding in arylsulfatase G-deficient mice: Similarities and dissimilarities to Sanfilippo disease (mucopolysaccharidosis type III)","volume":"24","author":"Kowalewski","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7481","DOI":"10.1158\/0008-5472.CAN-11-0940","article-title":"Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells","volume":"71","author":"Li","year":"2011","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4764","DOI":"10.1073\/pnas.0910872107","article-title":"Cholesterol trafficking is required for mTOR activation in endothelial cells","volume":"107","author":"Xu","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrm3522","article-title":"Amino acid signalling upstream of mTOR","volume":"14","author":"Jewell","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1212\/WNL.0000000000002041","article-title":"Acetyl-dl-leucine in Niemann-Pick type C: A case series","volume":"85","author":"Bremova","year":"2015","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/humu.23184","article-title":"Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations","volume":"38","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/acel.12409","article-title":"Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages","volume":"15","author":"Aflaki","year":"2016","journal-title":"Aging Cell."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1194\/jlr.M066522","article-title":"Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes","volume":"57","author":"Guo","year":"2016","journal-title":"J. Lipid. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.3389\/fphys.2018.01663","article-title":"New Approaches to Tay-Sachs Disease Therapy","volume":"9","author":"Solovyeva","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ymgme.2014.11.015","article-title":"Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses","volume":"114","author":"Anguiano","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/j.jaci.2018.01.018","article-title":"Autophagic dysfunction in patients with Papillon-Lef\u00e8vre syndrome is restored by recombinant cathepsin C treatment","volume":"142","author":"Giampieri","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1080\/15548627.2016.1274850","article-title":"Involvement of lysosomal dysfunction in autophagosome accumulation and early pathologies in adipose tissue of obese mice","volume":"13","author":"Mizunoe","year":"2017","journal-title":"Autophagy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"962","DOI":"10.2353\/ajpath.2007.070052","article-title":"Cholesterol accumulation is associated with lysosomal dysfunction and autophagic stress in Npc1 \u2212\/\u2212 mouse brain","volume":"171","author":"Liao","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1126\/science.1174447","article-title":"A gene network regulating lysosomal biogenesis and function","volume":"325","author":"Sardiello","year":"2009","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1172\/JCI121277","article-title":"PTEN-opathies: From biological insights to evidence-based precision medicine","volume":"129","author":"Yehia","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"20483","DOI":"10.1074\/jbc.M602180200","article-title":"Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis","volume":"281","author":"Cao","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1016\/j.cub.2012.06.055","article-title":"Drosophila TRPML is required for TORC1 activation","volume":"22","author":"Wong","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liebau, M.C., Braun, F., H\u00f6pker, K., Weitbrecht, C., Bartels, V., M\u00fcller, R.U., Brodesser, S., Saleem, M.A., Benzing, T., and Schermer, B. (2013). Dysregulated autophagy contributes to podocyte damage in Fabry\u2019s disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063506"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3389\/fendo.2014.00127","article-title":"Podocyte pathology and nephropathy\u2014sphingolipids in glomerular diseases","volume":"5","author":"Merscher","year":"2014","journal-title":"Front. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1111\/tra.12613","article-title":"Lysosomal membrane permeabilization and cell death","volume":"19","author":"Wang","year":"2018","journal-title":"Traffic"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1038\/1881000a0","article-title":"Membraneous cytoplasmic granules in infantile amaurotic idiocy","volume":"188","author":"Terry","year":"1960","journal-title":"Nature"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3122\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:28:35Z","timestamp":1760167715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,11]]},"references-count":35,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cells10113122"],"URL":"https:\/\/doi.org\/10.3390\/cells10113122","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.05.28.446132","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,11]]}}}