Tay–Sachs Disease

Abstract

GM2 gangliosidosis is a family of three diseases that include Tay–Sachs disease (described over a century ago), Sandhoff disease and the AB‐variant form, reflecting the need of three gene products to hydrolyse GM2 ganglioside. The recent elucidation of the crystal structures these three proteins have provided a better understanding of the molecular basis of GM2 gangliosidosis. The discovery that most deleterious missense mutations affect the folding or the assembly of the heterodimeric enzyme, and that delays in these processes invoke premature degradation by the endoplasmic reticulum‐quality control system, have suggested a novel therapeutic approach, enzyme enhancement therapy, for some forms of this and other genetic diseases. Progress is also being made on developing a more generally applicable approach, based on gene therapy, for Tay–Sachs and Sandhoff disease. If successful, this will also serve as a model for developing similar therapies for other diseases with neurological involvement. Key Concepts: The history of research into Tay–Sachs disease demonstrates the power of the classical scientific approach to problem solving involving building, over many decades, on the contributions from scientists with diverse interests and expertise. The study or rare diseases often lead to unexpected discoveries of broader‐based metabolic pathways and disease mechanisms. The study of rare diseases can also lead to the development of novel therapeutic approaches that can be adapted to more common diseases.

Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase

“…Several different scaffolds of non-iminosugar GCase inhibitors have been reported as GCase pharmacological chaperones (PCs) since 2007 [12][13][14][15][16] (Figure 1). We found that a noninhibitory GCase PC NCGC00188758 217 can enhance GCase activity specifically within the lysosomal compartment, reduce GluCer and hexosylsphingosine substrates, and subsequently enhance the clearance of pathological α-synuclein 18 .…”

Characterization of recombinant human lysosomal beta-hexosaminidases produced in the methylotrophic yeast Pichia pastoris

“…Tay Sachs (TSD, OMIM #272800) and Sandhoff (SD, OMIM #268800) diseases are lysosomal storage disorders (LSD) known as GM2 Gangliosidosis. They are autosomal recessive disorders caused by mutations in HEXA or HEXB genes, which encode for the α-or β-subunits, respectively, of the human lysosomal β-N-acetylhexosaminidases (Hex, EC 3.2.1.52) A, B, or S [1,2]. TSD and SD are clinically indistinguishable, except that in SD central nervous system (CNS) and visceral organs are affected, whereas in TSD only the CNS is impaired.…”

Human recombinant lysosomal β‐Hexosaminidases produced in Pichia pastoris efficiently reduced lipid accumulation in Tay‐Sachs fibroblasts

“…However, in SD the central nervous system (CNS) and visceral organs are affected, whereas in TSD only the CNS is impaired. Patients' lifespan varies from 1 to 5 years in the severe infantile form, to late teens for patients with the juvenile form; while it is still unclear if there is a reduction in the lifespan for the late‐onset patients with the disease (Cachon‐Gonzalez, Zaccariotto, & Cox, 2018; Gravel et al, 2001; Tropak & Mahuran, 2010).…”