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:	Beatriz Castejón-Vega, Alejandro Rubio, Antonio J. Pérez-Pulido, José L. Quiles, Jon D. Lane, Beatriz Fernández-Domínguez, María Begoña Cachón-González, Carmen Martín-Ruiz, Alberto Sanz, Timothy M. Cox, Elísabet Alcocer-Gómez, Mario D. Cordero
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	autophagy mTOR GM2 gangliosidosis L-arginine Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f52039e69fcc4dfe90d6e42e02924715
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spelling	oai:doaj.org-article:f52039e69fcc4dfe90d6e42e029247152021-11-25T17:11:45ZL-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation10.3390/cells101131222073-4409https://doaj.org/article/f52039e69fcc4dfe90d6e42e029247152021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3122https://doaj.org/toc/2073-4409Aims: 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.Beatriz Castejón-VegaAlejandro RubioAntonio J. Pérez-PulidoJosé L. QuilesJon D. LaneBeatriz Fernández-DomínguezMaría Begoña Cachón-GonzálezCarmen Martín-RuizAlberto SanzTimothy M. CoxElísabet Alcocer-GómezMario D. CorderoMDPI AGarticleautophagymTORGM2 gangliosidosisL-arginineBiology (General)QH301-705.5ENCells, Vol 10, Iss 3122, p 3122 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	autophagy mTOR GM2 gangliosidosis L-arginine Biology (General) QH301-705.5
spellingShingle	autophagy mTOR GM2 gangliosidosis L-arginine Biology (General) QH301-705.5 Beatriz Castejón-Vega Alejandro Rubio Antonio J. Pérez-Pulido José L. Quiles Jon D. Lane Beatriz Fernández-Domínguez María Begoña Cachón-González Carmen Martín-Ruiz Alberto Sanz Timothy M. Cox Elísabet Alcocer-Gómez Mario D. Cordero L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation
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	article
author	Beatriz Castejón-Vega Alejandro Rubio Antonio J. Pérez-Pulido José L. Quiles Jon D. Lane Beatriz Fernández-Domínguez María Begoña Cachón-González Carmen Martín-Ruiz Alberto Sanz Timothy M. Cox Elísabet Alcocer-Gómez Mario D. Cordero
author_facet	Beatriz Castejón-Vega Alejandro Rubio Antonio J. Pérez-Pulido José L. Quiles Jon D. Lane Beatriz Fernández-Domínguez María Begoña Cachón-González Carmen Martín-Ruiz Alberto Sanz Timothy M. Cox Elísabet Alcocer-Gómez Mario D. Cordero
author_sort	Beatriz Castejón-Vega
title	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_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_sort	l-arginine ameliorates defective autophagy in gm2 gangliosidoses by mtor modulation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f52039e69fcc4dfe90d6e42e02924715
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L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation

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