Autophagy and lysosomal dysfunction in Tay Sachs disease are restored by mTOR modulation

Tay-Sachs disease (TSD) is a inherited lysosomal storage disease resulting from mutations in the α-subunits of the lysosomal enzyme, β-hexosaminidase A, and leads to excessive accumulation of GM2 ganglioside. This disease can be presented in infantil, juvenil and adult forms with rapid, progressive neurodegeneration. Although the link between mTOR and autophagy in Taysachs diseases has not been previously examined, it is reasonably to infer that reduced activity of HexA and the consequent intracellular accumulation of undegraded ganglyosides could lead accumulation of lysosomes, other substrates or dysfunctional organelles, similar to other defects detected in other LSD. In the present study, we show that skin fibroblasts derived from PLS patients presented increased p62/SQSTM1 expression levels and autophagosome accumulation suggesting an impaired autophagic flux. We carry out a study of microarrays expression profiles in human samples under the following experimental conditions as well as possible alternative splicing events: healthy (HDFN), Sandhoff, Tay-sachs Infantile and Tay-sachs Juvenile