Tay–Sachs Disease


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.

Keywords: lysosomal storage disease; glycolipid metabolism; GM2 gangliosidosis; Sandhoff disease; AB‐variant; hexosaminidase; GM2 activator protein

Figure 1.

Dysmorphology of TSD neurons. A ‘membranous cytoplasmic body’ (MCB), as seen in an electron micrograph of a neuronal cell from a GM2 gangliosidosis patient. MCBs are enlarged lysosomes containing stored GM2 ganglioside.

Figure 2.

(a) Structure of GM2 ganglioside. Individual carbohydrates are colour coded according to the representation of GM2 ganglioside shown in the lower panel: N‐acetylgalactosamine (GalNAc, red hexagon); sialic acid (NANA, green hexagon), its carboxylate (–COO) contained in a small red circle; Gal (galactose, bule circle) and glucose (Glc, grey circle). (b) Overview of the roles of the two subunits of Hex A and the GM2 activator protein in the hydrolysis of GM2 ganglioside. C‐terminal ends of the α‐ (pink) and β‐ (light blue) subunits are denoted by the single letter ‘C’. Shown are the positions of Arg424 (denoted by +) in the active site (in grey) of the α‐subunit interacting with the carboxylate of the NANA residue of GM2 ganglioside and the equivalently positioned Asp452 (−) in the active site (grey) of the β‐subunit.

Figure 3.

Comparison and alignment of the amino acid sequences of the α‐ and β‐subunits of human Hex. Identical amino acids at aligned positions in the two subunits are denoted by asterisks (*). Sequences bearing the consensus sequon NXT/S, corresponding to sites of N‐linked glycosylation, are shown underlined. Signal sequences, removed co‐translationally from the N‐terminus of both subunits, are highlighted in blue above a dashed line. Sequences comprising the mature, lysosomal αp and βp chains are in square brackets [ ], those making up the αm and βb chains are in braces { } and those associated with the βa chain are in parentheses ( ). Disulfide bridges between Cys residues are indicated by connecting black lines beneath the secondary structural elements. Conserved motif (HXgGDE), found at the active site of Hex, is boxed outlined in red. The basic sequence (N‐R424) in the α‐subunit, involved in pairing with the carboxylate group of NANA, and its aligned acidic sequence (D‐L453) in the β‐subunit are shown boxed and outlined in blue. These are adjacent to αY427 and βY456 which are required for the stabilisation of their companion subunit's active site (see Figure ). Note that an indicated βY456S substitution has been associated with acute Sandhoff disease. The boundary between Domains I and II derived from the 3D structures of Hex B is demarcated by vertical lines labelled with the corresponding domain. Secondary structural elements found in the 3D structure of Hex B corresponding to α helices and β‐strands are denoted as green rectangular boxes and blue ribbons terminated with an arrowhead, respectively. Residues found at the interface between the α‐ and β‐subunits are highlighted in yellow. The figure was derived from Mark et al. .

Figure 4.

GM2 ganglioside computationally docked into the active site of Hex A. For clarity only selected residues in the active site interacting with GalNAc and parts of sialic acid (NANA) are shown. Residue Arg424 (highlighted in blue) in the active of the α‐subunit is highlighted, showing the bidentate hydrogen bonds formed with the negatively charged carboxylate group (arrow) from NANA. A negatively charged aspartic acid (Asp452) residue in the equivalent position in the active site of the β‐subunit would repel the similarly charged carboxylate group found in GM2. The stereogram was adapted, with permission, from Lemieux et al. .

Figure 5.

Proposed catalytic mechanism for Hex A/B and other members of glucoside hydrolase family GH20. Representations of the conserved catalytic acid/base residues in the active site of α‐ and β‐subunits are shown highlighted in pink and blue, respectively. A defining feature of the GH20 family members that retain the stereochemistry at the anomeric centre is that they use a substrate‐assisted catalysis mechanism to hydrolyse the glycosidic β‐linkage of the nonreducing N‐acetylhexosamide at the end of oligosaccharides, polysaccharides and glycolipids. The 2‐acetamido group on the substrate, along with the Asp (α322; β354) and Glu (β355;α323) residues (part of the conserved sequon, HXgGDE, see Figure ) located in the active site, act together to bring about hydrolysis of the substrate (Michaelis complex). According to this model, Glu acts as a general acid–base catalyst. Acting as an acid, it initially protonates the oxygen atom in the glycosidic linkage (first transition), thereby inducing a positive charge on the anomeric centre to form the first transition intermediate (oxazolinium ion intermediate) bearing a partial carbenium ion (positively charged carbon atom). Contemporaneously, the carboxylate anion in the Asp polarises the nitrogen atom on the acetamido group of the substrate, whereas at the same time orienting and partially ionising the carbonyl atom for nucleophillic attack of the carbon atom at the anomeric centre. These coordinated movements result in the formation of an oxazolinium intermediate (a stable thiazoline analogue of the intermediate, (NGT), which also functions as a nanomolar competitive inhibitor (Ki=200 nM) of lysosomal Hex A/B, provided initial experiment support for the existence of this intermediate) and release of the hydrolysed glycoconjugate (ROH). To complete the reaction, the ionised Glu now acts as a base and deprotonates an incoming water molecule producing a hydroxyl ion that attacks the anomeric carbon atom in the oxazolinium intermediate regenerating the 2‐acetamido group and re‐inverting the anomeric carbon atom to the original configuration (Product complex). Adapted, with permission, from Mark et al. .

Figure 6.

Three‐dimentional model of the quaternary Hex A:GM2 gaglioside:GM2 Activator complex. Two orientations of the complex (A and B) are related by 180° rotation about the z‐axis. Surface rendering of a model of Hex A showing the β‐subunit (dark grey) and a homology‐based model of α‐subunit (residues differing between α‐ and β‐subunits highlighted in light brown whereas shared identical residues are coloured in blue). Three‐dimensional ribbon representation of GM2 Activator (magenta) containing a bound molecule of GM2 ganglioside (yellow spheres). The hydrophobic tail of the ganglioside is docked into the cavity formed by the β‐cup fold of the Activator, and the GalNAc and NANA residues of GM2 are docked into the active site of the α‐subunit, the latter through its carboxylate group. The corresponding active site in the β‐subunit is highlighted in orange. Surface loops in the α‐subunit, capable of interacting with GM2 activator, are coloured green (αIleProVal:396–398) and magenta (αGlySerGluPro:280–283), respectively. Adapted, with permission, from Mark et al. .

Figure 7.

Flow chart depicting the biosynthesis, assembly and intracellular transport of the Hex isozymes. [Proα/β]UF indicates the concentration of unfolded α‐ or β‐propolypeptides, whereas [Proα/β]F indicates the concentration of either folded subunit. Transport from the cis‐Golgi to the trans‐Golgi network is through bulk flow, with secretion being the cell's default pathway. ER, endoplasmic reticulum; MPR, mannose phosphate receptor and ERGIC, ER Golgi intermediate compartment. Adapted, with permission, from Mahuran .



Aerts JM, Hollak CE, Boot RG et al. (2006) Substrate reduction therapy of glycosphingolipid storage disorders. Journal of Inherited Metabolic Disease 29: 449–456.

Alber T (1989) Mutational effects on protein stability. Annual Review of Biochemistry 58: 765–798.

Brown CA and Mahuran DJ (1993) β‐Hexosaminidase isozymes from cells co‐transfected with α and β cDNA constructs: analysis of α subunit missense mutation associated with the adult form of Tay‐Sachs disease. American Journal of Human Genetics 53: 497–508.

Cachon‐Gonzalez MB, Wang SZ, Lynch A et al. (2006) Effective gene therapy in an authentic model of Tay‐Sachs‐related diseases. Proceedings of the National Academy of Sciences of the USA 103: 10373–10378.

Chen B, Rigat B, Curry C et al. (1999) Structure of the GM2A gene: identification of an exon 2 nonsense mutation and a naturally occurring transcript with an in‐frame deletion of exon 2. American Journal of Human Genetics 65: 77–87.

Clarke JTR, Mahuran DJ, Sathe S et al. (2010) Open‐label phase I/II clinical trial of pyrimethamine for the treatment of chronic GM2 gangliosidosis. Molecular Genetics and Metabolism (in press).

Conzelmann E and Sandhoff K (1978) AB variant of infantile GM2 gangliosidosis: deficiency of a factor necessary for stimulation of hexosaminidase A‐catalyzed degradation of ganglioside GM2 and glycolipid GA2. Proceedings of the National Academy of Sciences of the USA 75: 3979–3983.

Desnick RJ (2004) Enzyme replacement and enhancement therapies for lysosomal diseases. Journal of Inherited Metabolic Disease 27: 385–410.

Dill KD and Shortle D (1991) Denatured states of proteins. Annual Review of Biochemistry 60: 795–825.

Edgington SM (1992) Rites of passage: moving biotech proteins through the ER. Biotechnology 10: 1413–1420.

Gravel RA, Clarke JTR, Kaback MM et al. (1995) The GM2 gangliosidoses. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Basis of Inherited Disease, vol. 2, pp. 2839–2879. New York: McGraw‐Hill.

Henrissat B and Bairoch A (1993) New families in the classification of glycosyl hydrolases based on amino acid sequence similarities. Biochemical Journal 293: 781–788.

Hou Y, Vocadlo D, Withers S et al. (2000) Role of beta Arg211 in the active site of human beta‐hexosaminidase B. Biochemistry 39: 6219–6227.

Huang JQ, Trasler JM, Igdoura S et al. (1997) Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay‐Sachs and Sandhoff diseases. Human Molecular Genetics 6: 1879–1885.

Jeyakumar M, Butters TD, Cortina‐Borja M et al. (1999) Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N‐butyldeoxynojirimycin. Proceedings of the National Academy of Sciences of the USA 96: 6388–6393.

Kresse H, Fuchs W, Glossl J et al. (1981) Liberation of N‐acetylglucosamine‐6‐sulfate by human beta‐N‐acetylhexosaminidase A. Journal of Biological Chemistry 256: 12926–12932.

Lemieux MJ, Mark BL, Cherney MM et al. (2006) Crystallographic structure of human beta‐hexosaminidase A: interpretation of Tay‐Sachs mutations and loss of G(M2) ganglioside hydrolysis. Journal of Molecular Biology 359: 913–929.

Maegawa GH, Banwell BL, Blaser S et al. (2009a) Substrate reduction therapy in juvenile GM2 gangliosidosis. Molecular Genetics and Metabolism 98: 215–224.

Maegawa GHB, Tropak M, Butner J et al. (2007) Pyrimethamine as a potential pharmacological chaperone for late‐onset forms of GM2 gangliosidosis. Journal of Biological Chemistry 282: 9150–9161.

Maegawa GHB, Tropak MB, Buttner JD et al. (2009b) Identification and characterization of ambroxol as an enzyme‐enhancement agent for Gaucher disease. Journal of Biological Chemistry 284: 23502–23516.

Mahuran DJ (1998) The GM2 activator protein, its roles as a co‐factor in GM2 hydrolysis and as a general glycolipid transport protein. Biochimica et Biophysica Acta 1393: 1–18.

Mahuran DJ (1999) Biochemical consequences of mutations causing the GM2 gangliosidoses. Biochimica et Biophysica Acta 1455: 105–138.

Maier T, Strater N, Schuette CG et al. (2003) The X‐ray crystal structure of human beta‐hexosaminidase B provides new insights into Sandhoff disease. Journal of Molecular Biology 328: 669–681.

Mark BL, Mahuran DJ, Cherney MM et al. (2003) Crystal structure of human beta‐hexosaminidase B: understanding the molecular basis of Sandhoff and Tay‐Sachs disease. Journal of Molecular Biology 327: 1093–1109.

Martin DR, Krum BK, Varadarajan GS et al. (2004) An inversion of 25 base pairs causes feline GM2 gangliosidosis variant. Experimental Neurology 187: 30–37.

Ni M and Lee AS (2007) ER chaperones in mammalian development and human diseases. FEBS Letters 581: 3641–3651.

Pons T, Olmea O, Chinea G et al. (1998) Structural model for family 32 of glycosyl‐hydrolase enzymes. Proteins 33: 383–395.

Shapiro BE, Pastores GM, Gianutsos J et al. (2009) Miglustat in late‐onset Tay‐Sachs disease: a 12‐month, randomized, controlled clinical study with 24 months of extended treatment. Genetics in Medicine 11: 425–433.

Sharma R, Deng H, Leung A et al. (2001) Identification of the 6‐sulfate binding site unique to α‐subunit‐containing isozymes of human β‐hexosaminidase. Biochemistry 40: 5440–5446.

Tews I, Perrakis A, Oppenheim A et al. (1996) Bacterial chitobiase structure provides insight into catalytic mechanism and the basis of Tay‐Sachs disease. Nature Structural Biology 3: 638–648.

Triggs‐Raine BL, Akerman BR, Clarke JT et al. (1991) Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay‐Sachs disease. American Journal of Human Genetics 49: 1041–1054.

Trombetta ES and Parodi AJ (2003) Quality control and protein folding in the secretory pathway. Annual Review of Cell & Developmental Biology 19: 649–676.

Tropak MB, Blanchard J, Withers SG et al. (2007) High‐throughput screening for novel human lysosomal beta‐N‐acetyl hexosaminidase inhibitors acting as pharmacological chaperones. Chemistry and Biology 14: 153–164.

Tropak MB, Bukovac SW, Rigat BA et al. (2010) A sensitive fluorescence‐based assay for monitoring GM2 ganglioside hydrolysis in live patient cells and their lysates. Glycobiology 20: 356–365.

Tropak MB, Kornhaber GJ, Rigat BA et al. (2008) Identification of pharmacological chaperones for Gaucher disease and characterization of their effects on β‐glucocerebrosidase by hydrogen/deuterium exchange mass spectrometry. ChemBioChem 9: 2650–2662.

Tropak MB and Mahuran D (2007) Lending a helping hand, screening chemical libraries for compounds that enhance β‐hexosaminidase A activity in GM2 gangliosidosis cells. FEBS Journal 274: 4951–4961.

Tropak MB, Reid S, Guiral M et al. (2004) Pharmacological enhancement of β‐hexosaminidase activity in fibroblasts from adult Tay‐Sach and Sandhoff patients. Journal of Biological Chemistry 279: 13478–13487.

Wakamatsu N, Kobayashi H, Miyatake T et al. (1992) A novel exon mutation in human β‐hexosaminidase β subunit gene affecting the 3′ splice site selection. Journal of Biological Chemistry 267: 2406–2413.

Wendeler M, Werth N, Maier T et al. (2006) The enzyme‐binding region of human GM2‐activator protein. FEBS Journal 273: 982–991.

Williams SJ, Mark BL, Vocadlo DJ et al. (2002) Aspartate 313 in the Streptomyces plicatus hexosaminidase plays a critical role in substrate‐assisted catalysis by orienting the 2‐acetamido group and stabilizing the transition state. Journal of Biological Chemistry 277: 40055–40065.

Wright CS, Li SC and Rastinejad F (2000) Crystal structure of human GM2‐activator protein with a novel beta‐cup topology. Journal of Molecular Biology 304: 411–422.

Wu BM, Tomatsu S, Fukuda S et al. (1994) Overexpression rescues the mutant phenotype of L176F mutation causing beta‐glucuronidase deficiency mucopolysaccharidosis in two Mennonite siblings. Journal of Biological Chemistry 269: 23681–23688.

Zarghooni M, Bukovac S, Tropak M et al. (2004) An alpha‐subunit loop structure is required for GM2 activator protein binding by beta‐hexosaminidase A. Biochemical & Biophysical Research Communications 324: 1048–1052.

Further Reading

Ballabio A and Gieselmann V (2009) Lysosomal disorders: from storage to cellular damage. Biochimica et Biophysica Acta 1793: 684–696.

Bernales S, Papa FR and Walter P (2006) Intracellular signaling by the unfolded protein response. Annual Review of Cell & Developmental Biology 22: 487–508.

Lee JH, Yu WH, Kumar A et al. (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer‐related PS1 mutations. Cell 141: 1146–1158.

Settembre C, Fraldi A, Jahreiss L et al. (2008) A block of autophagy in lysosomal storage disorders. Human Molecular Genetics 17: 119–129.

Vellodi A (2005) Lysosomal storage disorders. British Journal of Haematology 128: 413–431.

Winslow AR and Rubinsztein DC (2008) Autophagy in neurodegeneration and development. Biochimica et Biophysica Acta 1782: 723–729.

Wiseman RL, Powers ET, Buxbaum JN et al. (2007) An adaptable standard for protein export from the endoplasmic reticulum. Cell 131: 809–821.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Tropak, Michael, and Mahuran, Don J(Dec 2010) Tay–Sachs Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006019.pub2]