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

Research Laboratory, Oral Medicine Department, University of Sevilla, 41009 Sevilla, Spain
Centro Andaluz de Biologia del Desarrollo (CABD, UPO-CSIC-JA), Facultad de Ciencias Experimentales (Área de Genética), Universidad Pablo de Olavide, 41013 Sevilla, Spain
Department of Physiology, Institute of Nutrition and Food Technology “José Mataix Verdú”, Biomedical Research Center, University of Granada, 18071 Granada, Spain
Cell Biology Laboratories, School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK
Acción y Cura Para Tay-Sachs (ACTAYS), 28220 Madrid, Spain
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
Biosciences Institute, Newcastle University, Newcastle upon Tyne NE4 5 PL, UK
Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UK
Departamento de Psicología Experimental, Facultad de Psicología, Universidad de Sevilla, 41009 Seville, Spain
Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), 11009 Cadiz, Spain
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28220 Madrid, Spain
Author to whom correspondence should be addressed.
Academic Editors: Christian Münz and Mireille Verdier
Cells 2021, 10(11), 3122;
Received: 13 October 2021 / Revised: 9 November 2021 / Accepted: 10 November 2021 / Published: 11 November 2021
(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Autophagy)
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. View Full-Text
Keywords: autophagy; mTOR; GM2 gangliosidosis; L-arginine autophagy; mTOR; GM2 gangliosidosis; L-arginine
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Figure 1

MDPI and ACS Style

Castejón-Vega, B.; Rubio, A.; Pérez-Pulido, A.J.; Quiles, J.L.; Lane, J.D.; Fernández-Domínguez, B.; Cachón-González, M.B.; Martín-Ruiz, C.; Sanz, A.; Cox, T.M.; Alcocer-Gómez, E.; Cordero, M.D. L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation. Cells 2021, 10, 3122.

AMA Style

Castejón-Vega B, Rubio A, Pérez-Pulido AJ, Quiles JL, Lane JD, Fernández-Domínguez B, Cachón-González MB, Martín-Ruiz C, Sanz A, Cox TM, Alcocer-Gómez E, Cordero MD. L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation. Cells. 2021; 10(11):3122.

Chicago/Turabian Style

Castejón-Vega, Beatriz, 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, and Mario D. Cordero. 2021. "L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation" Cells 10, no. 11: 3122.

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