Overall Description of the Disease

Who it Affects
Tay-Sachs disease is a rare hereditary neurodegenerative disorder which means that it highly
compromises the nervous system since its cells either stop working or simply die. Its most
common form is found within infants of around 6 months but is also found in the juvenile form
where it presents itself in children of around 5 years old. Moreover, there also exists a form of
Tay-Sachs that affects teenagers and older individuals known as late-onset Tay Sachs diseases
(LOTS). All these forms are hereditary, meaning that it is passed down from parents to their
children in an autosomal recessive manner (Renna et al., 2021). In other words, the child
receives the mutated gene, which is the HEXA gene in this case, from both parents (Mayo
Clinic, 2022). This essay will be focusing on the infant form since it is the most common, but it
is worth noting that all the forms are similar and share many symptoms as they arise from the
same mutation.

Cause
Tay-Sachs is caused by a mutation in the hexosaminidase subunit alpha (HEXA) gene. The latter
codes for the HEXA protein which is a building block of the larger enzyme beta-hexosaminidase
A (Renna et al., 2021). Due to this change, the latter is no longer capable of breaking GM2
ganglioside which is a fatty substance. As a result, it builds up and damages nerve cells in the
brain and spinal cord in which it is found (Mayo Clinic, 2022). In the infantile form,
hexosaminidase A is completely absent which makes it the most severe out of all three since no
amount of GM2 ganglioside is broken down unlike the other two forms where the faint amount
of hexosaminidase A is able to do so but in small amounts (Renna et al., 2021).

Symptoms
Generally, Tay-Sachs is associated with motor and sense problems and affects both males and
females. In its most common form, symptoms first appear when the infant is around three to six
months. These include muscle weakness, muscles twitches and a big exaggerated response to
sudden noise. A few months later, new symptoms, such as muscle spasms, unusual eye
movements and stiff movements, appear. One of these is the development of a red spot (Fig. 1)
on the macula, a part of the eye, which presents itself in around 90% of infantile Tay-Sachs
cases. As time goes on, new more serious problems arise. Indeed, as the infants grow older,
seizures, difficulty swallowing, loss of vision and hearing and paralysis appear. These continue
to grow more serious to the point of becoming life-threatening. As a result, individuals around
three to five years old can develop aspiration pneumonia which leads to respiratory failure
(Renna et al., 2021).

Fig. 1. Cherry-Red Spot on the Macula

https://eyewiki.org/Cherry-Red_Spot

Treatment
To this day, no cure has been found to treat Tay-Sachs. Consequently, treatment is focused on
managing and alleviating the symptoms. However, there are currently studies in progress to find
a treatment through, for example, enzymatic replacement therapy which aims to replace the
defective beta-hexosaminidase A (Renna et al., 2021).
Molecular Mechanism Behind the Disease

Normal function
Beta-hexosaminidase A (Hex A) is found in lysosomes which are components of the cell
responsible for breaking down toxic substances but also functions as a recycling center for the
“defective” parts of the cell. It plays a pivotal role in the brain as well as the spinal cord, which
basically constitutes the basis of the central nervous system, as it breaks down the fatty substance
GM2 ganglioside (MedlinePlus, 2021).

Located in neuronal cells, gangliosides are complex glycolipids that have many important
biological functions that are essential to the correct functioning of the central nervous system.
GM2 gangliosides make up about 5% of all gangliosides. The accumulation of these specific
types of gangliosides have deadly effects as they often cause neuronal death due the cytotoxic
effects it induces (Leal et al., 2020) . Beta-hexosaminidase A prevents this by hydrolyzing GM2
ganglioside. More precisely, “it removes the terminal non-reducing N-acetylgalactosamine
(GalNAc) from the GM2 ganglioside” (Lemieux et al., 2006).

Beta-hexosaminidase A is found within the Family 20 glycoside hydrolases (glycosidase). It is

composed of three subunits: alpha-subunit, beta-subunit and the small monomeric GM2 activator
(GM2A) (Fig. 2-3). The activator “is a lipid transporter that removes GM2 from its membranous
environment and presents it to Hex A for hydrolysis” (Lemieux et al., 2006). In certain proteins,
neutral glycolipids and mucopolysaccharides, both Hex A and Hex B (a beta-homodimeric Hex
isozyme) can hydrolyze GalNAc and/or N-acetylglucosamine (GlcNAc) from substrates.
However, in the specific case of GM2 ganglioside, only Hex A is capable of carrying out its
hydrolysis (Lemieux et al., 2006).
Fig. 2 3D Structure of beta-hexosaminidase Fig. 3 3D Structure of the Monomeric GM2
A where the beta chain is in orange and the Activator Protein
alpha chain is in green https://www.rcsb.org/structure/2ag4
https://www.ebi.ac.uk/pdbe/entry/pdb/2gjx

Both the alpha and beta subunit are post-translationally cleaved. Then, the alpha-subunit of Hex
A consists of two polypeptide chains: αLys23 to αGly74, and αThr89 to αGln528. In the case of
the beta-subunit, it is composed of three polypeptide chains: βAla50 to βGly107, βThr122 to
βSer311, and βLeu316 to βMet556. Both of them also possess one active site which contains the
general acid-base glutamate residue which is essential in the cleaving of the GalNAc residues
from GM2 gangliosides . Moreover, they are similar as their sequence matches with a 60% rate
(Lemieux et al., 2006). As for the monomeric GM2 activator protein, it is made of an
“eight-stranded β-cup fold organized around a spacious open hydrophobic cavity suitable for
lipid binding” (Wright et al., 2003). This is consistent with its role which is to bring the fatty
substance GM2 ganglioside to Hex A for it to be hydrolyzed.

Dysfunction
Tay-Sachs is caused by a mutation of the HEXA gene which codes for the alpha-subunit of Hex
A. This then leads to the loss or inactivation of Hex A. The mutation of the HEXA gene is
caused by many mutations such as missense/nonsense, splicing, small and gross deletions. “For
HEXA the most representative mutation is the transition c.533 G > A that changes arginine by
histidine” (Leal et al., 2020). Consequently, this alters the catalytic site of the alpha-subunit
which significantly negatively affects its function and stability. Missense mutations like these are
also a major factor in causing the dysfunction of Hex A.

The majority of the mutations in Hex A shifts the equilibrium from the fully and correctly folded
form to a misfolded form. This leads to the retention of the alpha-subunit in the endoplasmic
reticulum (ER) in which it is degraded through the ER-associated degradation (ERAD) pathway.
In this process, misfolded proteins are detected by ER proteins and are brought back to the
cytosol where they undergo ubiquitination and are targeted for degradation by the proteasome
(Lemieux et al., 2006).

Due to the many possible missense mutations, different extents vary. For example, the B1
mutation which occurs mostly at αArg178 results in the formation of a “normal” Hex A
heretodimer but which is incapable of hydrolyzing GM2 ganglioside. Normally, αArg178 is
bound to the 3’ hydroxyl group of GalNAc (Fig. 4). However, the mutations in αArg178 cause a
disruption in the hydrogen bonds in the active site that “reduce GM2 binding and severely affect
the activity of the mutant α-active site of Hex A” (Lemieux et al., 2006). Consequently, Hex A is
no longer capable of properly hydrolyzing GM2 gangliosides.
 Fig. 4 Binding of αArg178 and GalNAc
https://pmc.ncbi.nlm.nih.gov/articles/PMC2910082/#:~:text=Two%20distinct%20active%20sites
%20are,through%20structure%2Dbased%20drug%20design.
References
Renna et al. National Organization for Rare Disorders. (2021, May 21). Tay Sachs Disease.
NORD. https://rarediseases.org/rare-diseases/tay-sachs-disease/

Mayo Clinic. (2022, January 21). Tay-Sachs disease. Mayo Clinic.

https://www.mayoclinic.org/diseases-conditions/tay-sachs-disease/symptoms-causes/syc-
20378190

MedlinePlus. (2022, October 13). Tay-Sachs disease. U.S. National Library of Medicine.
Retrieved December 11, 2024, from https://medlineplus.gov/ency/article/001417.htm

Leal, A. F., Benincore-Flórez, E., Solano-Galarza, D., Jaramillo, R. G. G., Echeverri-Peña, O. Y.,
Suarez, D. A., Alméciga-Díaz, C. J., & Espejo-Mojica, A. J. (2020). GM2
Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies.
International Journal of Molecular Sciences, 21(17), 6213.
https://doi.org/10.3390/ijms21176213

Lemieux, M. J., Mark, B. L., Cherney, M. M., Withers, S. G., Mahuran, D. J., & James, M. N.
(2006). Crystallographic structure of human Β-Hexosaminidase A: Interpretation of
Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis. Journal of Molecular
Biology, 359(4), 913–929. https://doi.org/10.1016/j.jmb.2006.04.004

Wright, Christine Schubert, Zhao, Qiang, Rastinejad, Fraydon. (2003). Structural Analysis of
Lipid Complexes of GM2-Activator Protein. Journal of Molecular Biology, 331(4),
951-964. https://doi.org/10.1016/S0022-2836(03)00794-0