Tay-Sachs Disease HEXA

Tay-Sachs Disease HEXA

HEXA and Tay-Sachs Disease Presented by: Yi Sin Tee http://www.ldnz.org.nz/news_and_issues/conference_reports/national_tay_sachs_and_allied_diseases Background on Tay-Sachs Disease (TSD) Autosomal recessive disorder Due to missing Hexoaminidase A (an enzyme

that remove acetylglucosamine residues from polysaccharides) Carrier rate: 1 in 300 Occurrence in Eastern European, Central European and Askhenazi Jewish heritage Model for the lysosomal metabolism of GM2 Hex A

- heterodimer - interact with GM2 indirectly. - Remove the terminal Nacetylgalactosamine from GM2 GM2 activator protein - Extracts the glycolipid Activator-lipid complex http://www.sciencedirect.com/science/article/pii/S1357431098012271 http://www.utm.utoronto.ca/~w3bio315/lecture15.htm

Types of TSD Information adapted from National Tay-Sachs & Allied Diseases What are the symptoms of TSD?

Loss of muscle coordination Speech problems Seizures Mental retardation

Paralysis Dementia Eye abnormality cherry-red spot Figure from http://flipper.diff.org/app/items/info/2950 Location of HEXA gene Figure from Genetics Home Reference

Mutations of the HEXA gene reduce the activity of -hexosaminidase A (Hex A) HEXA protein domain Two domains were found on the HEXA sequence by SMART. Active site

Two domains were found in HEXA protein by Pfam. Glycoside hydrolase family 20, domain 2 Glycoside hydrolase family 20, catalytic domain How is HEXA associated with TSD? TSD is caused by a mutation that leaves the

body unable to produce an enzyme known as hexosaminidase-A (Hex-A). Fat metabolism in nerve cells. By the absence of this enzyme, central nervous system degeneration ensues due to the accumulation of lipid called GM2 ganglioside in the nerve cells of the brain How is HEXA associated with TSD?

TSD is caused by a mutation that leaves the body unable to produce an enzyme known as hexosaminidase-A (Hex-A). Fat metabolism in nerve cells. By the absence of this enzyme, central nervous system degeneration ensues due to the accumulation of lipid called GM2 ganglioside in the nerve cells of the brain

Organism Phenotypes Hexa -/- mice show the neuropathology characteristic of Tay-Sachs disease. (A) Membranous cytoplasmic bodies (MCBs) in the parietal cortex. (B) Neurons are immunostained with anti-Gm2 ganglioside

antibody. (C) Multilayered lamellae in a cerebral cortical neuron http://www.ncbi.nlm.nih.gov/pmc/articles/PMC44940/pdf/pnas01143-0320.pdf Organism Phenotypes Phenotype of Late Onset TSD (LOTS) mice.

(A) The phenotype of a presymptomatic 8-month old bred female (B) A symptomatic 18-month-old bred female Jeyakumar, M. , Smith, D. , Eliott-Smith, E. , Cortina-Borja, M. , Reinkensmeier, G. , et al. (2002). An inducible mouse model of late onset tay-sachs disease. Neurobiology of Disease, 10(3), 201-210 Why use a mouse model? Human protein domain HEXA

Mouse protein domain Hexa Identities = 84% The mutant phenotypes expressed in the mice are the closest characteristics of the human Tay-Sachs disease.

Hexa Protein Phylogeny Phylogenetic tree made using ClustalW2 Hexa Protein Phylogeny Phylogenetic tree made using Phylogeny.fr HEXA Interaction Network

http://string.embl.de/newstring_cgi/show_network_section.pl Experimental Questions 1. What is the Gene Ontology (GO) for the proteins involved in the degradation of GM2 in the HEXA interaction network? 2. What domain are found in the related proteins located at the lysosome? Are

Glycoside hydrolase family 20, catalytic domain found in those protein? Experimental Questions 1. What is the Gene Ontology (GO) for the proteins involved in the degradation of GM2 in the HEXA interaction network? 2. What domain are found in the related proteins located at the lysosome? Are

Glycoside hydrolase family 20, catalytic domain found in those protein? (1) What is the GO for the proteins involved in the degradation of GM2 in the HEXA interaction network? Method: Using the AMIGO database to find out the gene ontology of each related proteins in the degradation of GM2 and

categorize them into different cellular component. (1) Hypothesis The GO for the related proteins in the HEXA interaction network is categorized based on cellular component. There are categorized into groups like lysosome, lysosomal lumen, membrane, nucleus, cytosol, Golgi apparatus,

and mitochondrial matrix. (1) Collected Data lysosome Lysosomal lumen Golgi apparatus

Mitochondrial matrix Nucleus http://string.embl.de/newstring_cgi/ show_network_section.pl Cytosol

Experimental Questions 1. What is the Gene Ontology (GO) for the proteins involved in the degradation of GM2 in the HEXA interaction network? 2. What domain are found in the related proteins located at the lysosome? Are Glycoside hydrolase family 20, catalytic domain found in those protein?

(2) What domain are found in the related proteins located at the lysosome? - Are Glycoside hydrolase family 20, catalytic domain found in those protein? Method: Using the SMART database to find the domains of the related proteins that are located in the lysosome. (2) Hypothesis

The Glycoside hydrolase family, catalytic domain should be observed in some of the proteins located at the lysosome in the HEXA interaction network because this domain play an important role in degrading GM2 ganglioside. (2) Collected Data HEXA

HEXB CHIT1 GLB1 (2) Expected Data NAGA

Melibiase GM2A Model for the lysosomal metabolism of GM2 Hex A - heterodimer - interact with GM2 indirectly.

- Remove the terminal Nacetylgalactosamine from GM2 GM2 activator protein - Extracts the glycolipid Activator-lipid complex http://www.sciencedirect.com/science/article/pii/S1357431098012271 Future Directions 1. What mechanism of action of GM2-AP causes the recognition of Hex-A?

Method: TAP-tag Label GM2-AP and determine how it is recognize HEXA 2. Chaperone Therapy - Different kind of chaperone to treat TSD with different mutant variations. 3. To create effective GM2 ganglioside inhibitors.

Conclusion Tay-Sachs Disease (TSD) is an autosomal recessive disease caused by mutations in both alleles of a gene (HEXA) on chromosome 15. The Glycoside hydrolase family 20, catalytic domain could play an important role in degrading GM2 ganglioside. References

1. Jeyakumar, M. , Smith, D. , Eliott-Smith, E. , Cortina-Borja, M. , Reinkensmeier, G. , et al. (2002). An inducible mouse model of late onset tay-sachs disease. Neurobiology of Disease, 10(3), 201-210. 2. Kabir, M. , Qadir, S. , Hassan, S. , Ahn, J. , & Wang, M. (4784). Rnai: An emerging field of molecular research. African Journal of Biotechnology, 7(25), 4784-4788. From http:// www.ajol.info/index.php/ajb/article/viewFile/59671/47957 3. MGI 4. Yamanaka, S. , Johnson, M. , Grinberg, A. , Westphal, H. , Crawley, J. , et al.

(1994). Targeted disruption of the hexa gene results in mice with biochemical and pathologic features of tay-sachs disease. Proceedings of the National Academy of Sciences of the United States of America, 91(21), 9975-9979. [ PUBMED] 5. National Tay-Sachs & Allied Diseases 6. String: http://string.embl.de 7. SMART: http://smart.embl-heidelberg.de/ 8. PFAM:http://pfam.sanger.ac.uk/

Video http:// www.cbs42.com/content/localnews/story/Littl e-Girl-Gets-Stem-Cell-Treatment-For-Deadly/g oY5hrZWkkS7yfOENWxsdA.cspx

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