L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation
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 neuron...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/11/3122 |
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| author | Beatriz Castejón-Vega 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 Mario D. Cordero |
| author_facet | Beatriz Castejón-Vega 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 Mario D. Cordero |
| author_sort | Beatriz Castejón-Vega |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T05:36:54Z |
| format | Article |
| id | doaj.art-f52039e69fcc4dfe90d6e42e02924715 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T05:36:54Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-f52039e69fcc4dfe90d6e42e029247152023-11-22T22:51:38ZengMDPI AGCells2073-44092021-11-011011312210.3390/cells10113122L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR ModulationBeatriz Castejón-Vega0Alejandro Rubio1Antonio J. Pérez-Pulido2José L. Quiles3Jon D. Lane4Beatriz Fernández-Domínguez5María Begoña Cachón-González6Carmen Martín-Ruiz7Alberto Sanz8Timothy M. Cox9Elísabet Alcocer-Gómez10Mario D. Cordero11Research Laboratory, Oral Medicine Department, University of Sevilla, 41009 Sevilla, SpainCentro Andaluz de Biologia del Desarrollo (CABD, UPO-CSIC-JA), Facultad de Ciencias Experimentales (Área de Genética), Universidad Pablo de Olavide, 41013 Sevilla, SpainCentro Andaluz de Biologia del Desarrollo (CABD, UPO-CSIC-JA), Facultad de Ciencias Experimentales (Área de Genética), Universidad Pablo de Olavide, 41013 Sevilla, SpainDepartment of Physiology, Institute of Nutrition and Food Technology “José Mataix Verdú”, Biomedical Research Center, University of Granada, 18071 Granada, SpainCell Biology Laboratories, School of Biochemistry, University of Bristol, Bristol BS8 1TD, UKAcción y Cura Para Tay-Sachs (ACTAYS), 28220 Madrid, SpainDepartment of Medicine, University of Cambridge, Cambridge CB2 0QQ, UKBiosciences Institute, Newcastle University, Newcastle upon Tyne NE4 5 PL, UKInstitute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UKDepartment of Medicine, University of Cambridge, Cambridge CB2 0QQ, UKDepartamento de Psicología Experimental, Facultad de Psicología, Universidad de Sevilla, 41009 Seville, SpainInstituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), 11009 Cadiz, SpainAims: 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.https://www.mdpi.com/2073-4409/10/11/3122autophagymTORGM2 gangliosidosisL-arginine |
| spellingShingle | Beatriz Castejón-Vega 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 Mario D. Cordero L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation Cells autophagy mTOR GM2 gangliosidosis L-arginine |
| title | L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation |
| title_full | L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation |
| title_fullStr | L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation |
| title_full_unstemmed | L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation |
| title_short | L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation |
| title_sort | l arginine ameliorates defective autophagy in gm2 gangliosidoses by mtor modulation |
| topic | autophagy mTOR GM2 gangliosidosis L-arginine |
| url | https://www.mdpi.com/2073-4409/10/11/3122 |
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