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

Lookup NU author(s): Dr Carmen Martin-RuizORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021 by the authors. Licensee MDPI, Basel, Switzerland.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. Conclusion: 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.

Publication metadata

Author(s): Castejon-Vega B, Rubio A, Perez-Pulido AJ, Quiles JL, Lane JD, Fernandez-Dominguez B, Cachon-Gonzalez MB, Martin-Ruiz C, Sanz A, Cox TM, Alcocer-Gomez E, Cordero MD

Publication type: Article

Publication status: Published

Journal: Cells

Year: 2021

Volume: 10

Issue: 11

Print publication date: 01/11/2021

Online publication date: 11/11/2021

Acceptance date: 10/11/2021

Date deposited: 24/11/2021

ISSN (electronic): 2073-4409

Publisher: MDPI


DOI: 10.3390/cells10113122


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Funder referenceFunder name
... number IS-BRC-1215-20014.
BBSRC project grant (BB/T016183/1)
Cure and Action for Tay-Sachs (CATS) Foundation: (UK charity 1144543)
grant from the Spanish Association of families affected by Tay–Sachs and Sandhoff disease (ACTAYS)
National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre grant ...