L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation
Authors
Castejón-Vega, Beatriz
Pérez-Pulido, Antonio J.
Lane, Jon D.
Fernández-Domínguez, Beatriz
Cachón-González, María Begoña
Sanz, Alberto
Alcocer-Gómez, Elísabet
Publication Date
2021-11-11Journal Title
Cells
Publisher
MDPI
Volume
10
Issue
11
Language
en
Type
Article
This Version
VoR
Metadata
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Castejón-Vega, B., Rubio, A., Pérez-Pulido, A. J., Quiles, J. L., Lane, J. D., Fernández-Domínguez, B., Cachón-González, M. B., et al. (2021). L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation. Cells, 10 (11) https://doi.org/10.3390/cells10113122
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. 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.
Keywords
autophagy, mTOR, GM2 gangliosidosis, L-arginine
Identifiers
External DOI: https://doi.org/10.3390/cells10113122
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330783
Rights
Licence:
https://creativecommons.org/licenses/by/4.0/
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