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 ß-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.

Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis.

Paediatric neurodegenerative diseases are frequently caused by inborn errors in glycosphingolipid (GSL) catabolism and are collectively termed the glycosphingolipidoses. GSL catabolism occurs in the lysosome and a defect in an enzyme involved in GSL degradation leads to the lysosomal storage of its substrate(s). GSLs are abundantly expressed in the central nervous system (CNS) and the disorders frequently have a progressive neurodegenerative course. Our understanding of pathogenesis in these diseases is incomplete and currently few options exist for therapy. In this review we discuss how mouse models of these disorders are providing insights into pathogenesis and also leading to progress in evaluating experimental therapies.

Increased density of the thalamus on CT scans in patients with GM2 gangliosidoses.

In 13 patients, the GM2 gangliosidoses, Sandhoff disease and Tay-Sachs disease, were found to be constantly associated with homogeneously and symmetrically increased CT attenuation within the thalami. In the only patient examined with MR imaging, a T2-weighted sequence showed hypointense thalami. It is suggested that this finding is caused by an accumulation of calcium, associated with the intracellular storage of GM2 ganglioside. The finding of dense thalami may be useful as a specific diagnostic criterion for GM2 gangliosidoses. In a few patients with blocks in adjacent steps in the sphingolipid metabolism, this finding was not present.