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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8619250 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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