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L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation

Aims: 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 neuron...

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Autores principales: Castejón-Vega, Beatriz, Rubio, Alejandro, Pérez-Pulido, Antonio J., Quiles, José L., Lane, Jon D., Fernández-Domínguez, Beatriz, Cachón-González, María Begoña, Martín-Ruiz, Carmen, Sanz, Alberto, Cox, Timothy M., Alcocer-Gómez, Elísabet, Cordero, Mario D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619250/
https://www.ncbi.nlm.nih.gov/pubmed/34831346
http://dx.doi.org/10.3390/cells10113122
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author Castejón-Vega, Beatriz
Rubio, Alejandro
Pérez-Pulido, Antonio J.
Quiles, José L.
Lane, Jon D.
Fernández-Domínguez, Beatriz
Cachón-González, María Begoña
Martín-Ruiz, Carmen
Sanz, Alberto
Cox, Timothy M.
Alcocer-Gómez, Elísabet
Cordero, Mario D.
author_facet Castejón-Vega, Beatriz
Rubio, Alejandro
Pérez-Pulido, Antonio J.
Quiles, José L.
Lane, Jon D.
Fernández-Domínguez, Beatriz
Cachón-González, María Begoña
Martín-Ruiz, Carmen
Sanz, Alberto
Cox, Timothy M.
Alcocer-Gómez, Elísabet
Cordero, Mario D.
author_sort Castejón-Vega, Beatriz
collection PubMed
description Aims: 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.
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spelling pubmed-86192502021-11-27 L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation Castejón-Vega, Beatriz Rubio, Alejandro Pérez-Pulido, Antonio J. Quiles, José L. Lane, Jon D. Fernández-Domínguez, Beatriz Cachón-González, María Begoña Martín-Ruiz, Carmen Sanz, Alberto Cox, Timothy M. Alcocer-Gómez, Elísabet Cordero, Mario D. Cells Article Aims: 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. MDPI 2021-11-11 /pmc/articles/PMC8619250/ /pubmed/34831346 http://dx.doi.org/10.3390/cells10113122 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Castejón-Vega, Beatriz
Rubio, Alejandro
Pérez-Pulido, Antonio J.
Quiles, José L.
Lane, Jon D.
Fernández-Domínguez, Beatriz
Cachón-González, María Begoña
Martín-Ruiz, Carmen
Sanz, Alberto
Cox, Timothy M.
Alcocer-Gómez, Elísabet
Cordero, Mario D.
L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation
title L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation
title_full L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation
title_fullStr L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation
title_full_unstemmed L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation
title_short L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation
title_sort l-arginine ameliorates defective autophagy in gm2 gangliosidoses by mtor modulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619250/
https://www.ncbi.nlm.nih.gov/pubmed/34831346
http://dx.doi.org/10.3390/cells10113122
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