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dc.contributor.authorCastejón-Vega, Beatriz
dc.contributor.authorRubio, Alejandro
dc.contributor.authorPérez-Pulido, Antonio J
dc.contributor.authorQuiles, José L
dc.contributor.authorLane, Jon D
dc.contributor.authorFernández-Domínguez, Beatriz
dc.contributor.authorCachón-González, María Begoña
dc.contributor.authorMartín-Ruiz, Carmen
dc.contributor.authorSanz, Alberto
dc.contributor.authorCox, Timothy M
dc.contributor.authorAlcocer-Gómez, Elísabet
dc.contributor.authorCordero, Mario D
dc.date.accessioned2022-01-07T18:56:59Z
dc.date.available2022-01-07T18:56:59Z
dc.date.issued2021-11-11
dc.identifier.issn2073-4409
dc.identifier.otherPMC8619250
dc.identifier.other34831346
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332448
dc.description.abstractAIMS: Tay-Sachs 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 β-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-Sachs 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.
dc.languageeng
dc.publisherMDPI AG
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 2073-4409
dc.sourcenlmid: 101600052
dc.subjectL-arginine
dc.subjectAutophagy
dc.subjectMtor
dc.subjectGm2 Gangliosidosis
dc.subjectLysosomes
dc.subjectFibroblasts
dc.subjectHumans
dc.subjectSandhoff Disease
dc.subjectTay-Sachs Disease
dc.subjectCathepsins
dc.subjectArginine
dc.subjectSignal Transduction
dc.subjectMutation
dc.subjectPermeability
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectGangliosidoses, GM2
dc.subjectHexosaminidase A
dc.subjectHexosaminidase B
dc.subjectTOR Serine-Threonine Kinases
dc.subjectTranscriptome
dc.subjectAutophagosomes
dc.titleL-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation.
dc.typeArticle
dc.date.updated2022-01-07T18:56:58Z
prism.issueIdentifier11
prism.publicationNameCells
prism.volume10
dc.identifier.doi10.17863/CAM.79894
dcterms.dateAccepted2021-11-10
rioxxterms.versionofrecord10.3390/cells10113122
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidRubio, Alejandro [0000-0002-6736-6141]
dc.contributor.orcidQuiles, José L [0000-0002-9048-9086]
dc.contributor.orcidMartín-Ruiz, Carmen [0000-0002-3361-6974]
dc.contributor.orcidCox, Timothy M [0000-0002-4951-9941]
dc.contributor.orcidCordero, Mario D [0000-0003-0151-3644]
dc.identifier.eissn2073-4409
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (RG50826 METABOLISM)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
cam.issuedOnline2021-11-11


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International