Autophagy dysfunctions and lysosomal permeabilization in Tay-Sachs and Sandhoff diseases

Resum

Autophagy is an essential intracellular process involved in survival, differentiation, development and cellular homeostasis. This catabolic mechanism supplies to the cell nutrients and energy to do its vital functions and gets rid of non-needed cellular components such as lipids, misfolded proteins and damage organelles. It consists on a multistep process highly regulated, conducted by autophagy-related proteins (ATGs), which starts by the formation of a vesicle which engulfs the material to be degraded to form an autophagosome following by the fusion to the lysosome. It contains the hydrolytic enzymes which are involve in the degradation of the cargo in the presence of an acidic environment (Levine & Kroemer, 2008). Dysfunction in the autophagy flux has been implicated in the progression of several diseases such as neurodegeneration, cancer and immune diseases, even in the normal ageing process. It is known that cell inability to degrade the cargo may lead to a defective autophagosome-lysosome fusion and thus, accumulation of autophagosome with non-degraded material inside the cells. This is the molecular base of a set of pathological conditions, known as lysosome storage disorder (LSD). Lysosomal dysfunction in most of these diseases is associated with impaired autophagic flux and autophagosome-lysosome fusion and a secondary accumulation of autophagy substrates such as SQSTM1/p62 and damage mitochondria. The key regulator of autophagy is mTOR which is involved in protein, lipid and nucleotide synthesis, lysosomal biogenesis, transcription, cytoskeletal rearrangements, energy metabolism, cell proliferation and survival. The presence of nutrients, growth factors and hypoxia induce mTOR promoting protein synthesis and cell growth and repressing autophagy. (Villanueva-Paz et al., 2016), (Munson & Ganley, 2015). Tay-Sachs and Sandhoff are two rare inherit LSDs which affect the nervous system and are characterized by early neuronal cell death and progressive neurodegeneration. They are caused by a mutation in a gene which encodes for the α (Tay-Sachs) and β (Sandhoff) subunit for the lysosome enzyme β-hexosaminidase A (HexA). This is the unique enzyme which is able to degrade a type of glycosphingolipids known as GM2 ganglioside. Consequently, there is an accumulation of them leading to cell death (Schuchman & Simonaro, 2013). The severity and progression of the diseases depend on the activity level of the dysfunctional enzyme and can be presented in infantile, juvenile and adult form with progressive neurodegeneration, hypotension, dysphagia, spasms, eye movement abnormalities, etc (Munson & Ganley, 2015). Nowadays, there is not an effective treatment beyond the palliative care. Although many mutations have been described, the molecular and cellular implications are still unknown. In the recent study, working with patient fibroblasts, it have been found low levels of mTOR pathway activation with the subsequent decreasing of protein synthesis and high levels of autophagy. However, it has been determined that the autophagy flux is impaired, with the accumulation of autophagosome with non-degrade material leading to the lysosomal permeabilization. Treatment of patient fibroblasts with L-arginine showed a partial recovery of cellular pathological alterations.