scholarly journals L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3122
Author(s):  
Beatriz Castejón-Vega ◽  
Alejandro Rubio ◽  
Antonio J. Pérez-Pulido ◽  
José L. Quiles ◽  
Jon D. Lane ◽  
...  

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.

2019 ◽  
Vol 67 (3) ◽  
pp. 323-329
Author(s):  
Carlos Andrés Gualdrón-Frías ◽  
Laura Tatiana Calderón-Nossa

Introduction: Lysosomal storage disease is caused by the deficiency of a single hydrolase (lysosomal enzymes). GM2 gangliosidoses are autosomal recessive disorders caused by deficiency of β-hexosaminidase and Tay-Sachs disease (TSD) is one of its three forms.Objective: To perform a review of the state of the art on TSD describing its definition, epidemiology, etiology, physiopathology, clinical manifestations and news in diagnosis and treatment.Materials and methods: A literature search was carried out in PubMed using the MeSH terms “Tay-Sachs Disease”.Results: 1 233 results were retrieved in total, of which 53 articles were selected. TSD is caused by the deficiency of the lysosomal enzyme β-hexosaminidase A (HexA), and is characterized by neurodevelopmental regression, hypotonia, hyperacusis and cherry-red spots in the macula. Research on molecular pathogenesis and the development of possible treatments has been limited, consequently there is no treatment established to date.Conclusion: TSD is an autosomal recessive neurodegenerative disorder. Death usually occurs before the age of five. More research and studies on this type of gangliosidosis are needed in order to find an adequate treatment.


2020 ◽  
Vol 144 ◽  
pp. 111575 ◽  
Author(s):  
Jing Lu ◽  
Jianing Lu ◽  
Yan Chen ◽  
Zhe Feng ◽  
Shuang Liu ◽  
...  

1995 ◽  
pp. 45-53
Author(s):  
Jaakko Ignatius

The frequency of marriages contracted between individuals with close consanguinity has traditionally been low in Finland. In the 19th and early 20th centuries only 0.1-0.3% of all marriages were contracted between first-cousins (average kinship coefficient 0.0001-0.0002). In genealogical search, however, a remote consanguinity (often beyond 3rd cousins) is frequently found especially in the rural areas and the true level of inbreeding is higher. In Finland, several autosomal recessive diseases are known to be enriched in the population. This unique spectrum of genetic diseases is sometimes called »the Finnish Disease Heritage». To study the implication of close consanguinity for these disorders, information on consanguineous marriages closer than second-cousins was collected from 808 families representing 24 different »Finnish» autosomal recessive disorders. The mean rate of first-cousin marriages was 1.6% (0-20%). Consanguinity (parents second-cousins or closer) was found in 4.2% of the families. For comparison, in 160 families representing three »non-Finnish» autosomal disorders the corresponding figures were 1.9% and 2.5%, respectively. Although these figures are high when compared to the general Finnish population, it can be concluded that close consanguinity is not a significant factor of Finnish genetic diseases.


2021 ◽  
Vol 21 ◽  
Author(s):  
Karlaina JL. Osmon ◽  
Patrick Thompson ◽  
Evan Woodley ◽  
Subha Karumuthil-Melethil ◽  
Cliff Heindel ◽  
...  

Background: GM2 gangliosidosis is a neurodegenerative, lysosomal storage disease caused by the deficiency of β-hexosaminidase A enzyme (HexA), an α/β-subunit heterodimer. A novel variant of the human hexosaminidase α-subunit, coded by HEXM, has previously been shown to form a stable homodimer, HexM, that hydrolyzes GM2 gangliosides (GM2) in vivo. Materials & Methods: The current study assessed the efficacy of intravenous (IV) delivery of a self-complementary adeno-associated virus serotype 9 (scAAV9) vector incorporating the HEXM transgene, scAAV9/HEXM, including the outcomes based on the dosages provided to the Sandhoff (SD) mice. Six-week-old SD mice were injected with either 2.5E+12 vector genomes (low dose, LD) or 1.0E+13 vg (high dose, HD). We hypothesized that when examining the dosage comparison for scAAV9/HEXM in adult SD mice, the HD group would have more beneficial outcomes than the LD cohort. Assessments included survival, behavioral outcomes, vector biodistribution, and enzyme activity within the central nervous system. Results: Toxicity was observed in the HD cohort, with 8 of 14 mice dying within one month of the injection. As compared to untreated SD mice, which have typical survival of 16 weeks, the LD cohort and the remaining HD mice had a significant survival benefit with an average/median survival of 40.6/34.5 and 55.9/56.7 weeks, respectively. Significant behavioral, biochemical and molecular benefits were also observed. The second aim of the study was to investigate the effects of IV mannitol infusions on the biodistribution of the LD scAAV9/HEXM vector and the survival of the SD mice. Increases in both the biodistribution of the vector as well as the survival benefit (average/median of 41.6/49.3 weeks) were observed. Conclusion: These results demonstrate the potential benefit and critical limitations of the treatment of GM2 gangliosidosis using IV delivered AAV vectors.


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