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

Beatriz Castejon Vega, Alejandro Rubio, Antonio Perez-Pulido, Jose Quiles, Jon D Lane, Beatriz Fernandez-Dominguez, Maria Cachon-Gonzales, Carmen Martin-Ruiz, Alberto Sanz, Timothy Cox, Elizabet Alcocer-Gomez, Mario Cordero*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

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 also 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
Original languageEnglish
Article number3122
JournalCells
Volume10
Issue number11
DOIs
Publication statusPublished - 11 Nov 2021

Bibliographical note

Funding 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.

Funding Information:
Funding: 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.

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

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