L-arginine ameliorates defective autophagy in GM2 gangliosidoses by mTOR modulation

Castejón-Vega, B. et al. (2021) L-arginine ameliorates defective autophagy in GM2 gangliosidoses by mTOR modulation. Cells, 10(11), 3122. (doi: 10.3390/cells10113122)

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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.

Item Type:Articles
Additional Information:This study was supported by a grant from the Spanish Association of families affected by Tay–Sachs and Sandhoff disease (ACTAYS), BBSRC project grant (BB/T016183/1), Cure and Action for Tay-Sachs (CATS) Foundation: (UK charity 1144543), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre grant number IS-BRC-1215-20014.
Glasgow Author(s) Enlighten ID:Sanz Montero, Professor Alberto and Castejon Vega, Miss Beatriz
Creator Roles:
Sanz, A.Formal analysis, Writing – review and editing
Authors: 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., and Cordero, M. D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Cells
ISSN (Online):2073-4409
Published Online:11 November 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Cells 10(11): 3122
Publisher Policy:Reproduced under a Creative Commons License

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