Tay – Sachs disease (TSD) is a type of lysosomal storage disorder in
which a defect in the α-subunit of the β-hexosaminidase A (HexA) enzyme results in accumulation of GM2 gangliosides in the lysosome. Accumulation within neuronal lysosomes results in neurodegeneration, symptoms associated with TSD, and typically results in death within 5 years for the infantile form. The HexA isozyme of β-hexosamindase is able to bind to the GM2 activator
protein (GM2AP), which is responsible for delivering the GM2 ganglioside to the HexA for hydrolysis. While specific key residues necessary for catalysis have been identified and recombinant enzymes for the use of enzyme replacement therapy (ERT) have been generated, there is no effective cure for TSD to this date.
The authors of the paper build on the work of Matsuoka et al., who argue that they were able to generate human hybrid Hex β-subunit that retains its stability, binds to the GM2AP, hydrolyzes the GM2 ganglioside, and can be delivered to the CNS using an adeno-associated virus. Verifying and building on this work, the authors constructed an identical Hex hybrid (H1) and a new hybrid (H2) containing additional α-sequences that may be important for GM2AP binding and compared the properties in cellulo with a GM2AP-dependent assay which utilizes a fluorescent GM2 derivative. After high expression of the enzymes was confirmed, it was found that hydrolysis of the GM2 derivative in a GM2AP-dependent manner was only accomplished if either subunit heterodimerized with expressed human α-subunit, suggesting that the α-subunit was responsible binding of the GM2AP-GM2 complex. Following characterization of enzymatic activity, the authors investigated the basis of Matsuoka et al.’s work, questioning the use of a detergent to activate the enzyme rather than the GM2AP and pointing out that they did not demonstrate their recombinant enzyme’s ability to bind to the GM2AP-GM2 complex. This work highlights that while there have been advancements in the generation of a recombinant β-subunit that retains its stability and is able to hydrolyze the ganglioside, there is still a need to identify the α-residues necessary to allow the β-hybrid to effectively bind the GM2-GM2AP complex for use in ERT.
Matsuoka K, Tamura T, Tsuji D, Dohzono Y, Kitakaze K, et al (2011) Therapeutic potential of intracerebroventircular replacement of modified human beta-hexosaminidase B for GM2 gangliosidosis. Mol Ther. 19: 1017 – 1024
For more information on Tay-Sachs Disease, visit this page: Infantile Tay-Sachs Disease. This page will provide a general overview of the disease and contain links for further reading.