Tay Sachs Disease

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Tay Sachs Disease

• By
• Ryan Sangiovanni

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Introduction

• Discovered and named after Warren Tay
• Tay-Sachs Disease is rare autosomal recessive
  genetic disorder
• Is the deficiency in ?-hexosaminidase A
• Different names are
• GM2 gangliosidosis
• Hexosaminidase A deficiency
• Sphingolipidosis

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Introduction

• Occurs when gangliosides build up in the nerve
  cells of the brain
• Ganglioside - fatty acid derivative (lipid)
• Is a genetic mutation on chromosome 15
• Lipid storage disorder that results from
  deficiency in Hexosaminidase A
• Commonly found in French Canadians and Ashkenazi
  Jews

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Different Types of ?-Hexosamindases

• Hexosaminidase A
• Produced in ER and transported to lysosome
• ER-gt Golgi apparatus-gt lysosome
• Hexosaminidase B
• Lacks ability to break GM2 gangliosides down
• So not a factor in Tay-Sachs
• Hexosaminidase S
• Only in Sandhoffs disease

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Variant Types of Tay-Sachs

• Variant B
• Mutated isoenzyme A of ?-HEX
• Capable of hydrolyzing GM2
• ? subunits
• Variant O
• Mutated HEXB not HEXA
• Variant AB
• ? subunits

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Symptoms

• Loss of hearing
• Physical and mental retardation
• Seizures
• Dementia
• And most noticeably detected by the red dots it
  causes on the retina of an individuals eye

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Different Types of Tay-Sachs

• Infantile acute form
• Most common and most fatal (by age of 5)
• Late infantile
• Delayed but still fatal
• Juvenile onset
• Anywhere from 6-16 yrs - crippling
• Adult onset
• 20-30 yrs - life shortening - slower progressing

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Structures
NANA
D-Galactose
D-Glucose
www.edinformatics.com
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Structures
N-acetylgalactosamine
Ceramide
www.edinformatics.com
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Metabolic Pathway
1. Voet, D. Voet, J.G. Biochemistry, 3rd edition

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3 Types of Gangliosides

• GM1 ganglioside
• Contains a galactose-N-acetylgalactosamine-galacto
  se-glucose to a ceramide
• GM2 ganglioside
• Same as GM1 but without a galactose
• GM3 ganglioside
• Same as GM2 but without an N-acetygalactosamine

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Gangliosides
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GM2-activator protein

• GM2-activator protein binds and lifts GM2 out of
  the membrane so that it can be recognized and
  cleaved by ?? dimer of hexosaminidase A
• In order for degradation via hydrolysis to occur
  the two subunits must be present and the
  activator protein must be present.

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GM2-activator protein
1. Voet, D. Voet, J.G. Biochemistry, 3rd edition

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GM2 gangliosides

• Mechanism for degradation by ?-Hexosaminidase A
• GM2 gangliosides attached to membrane
  phospholipids
• Forms complex
• Hydrolyzes
• Released to form GM3

www.bio.davidson.edu
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Biosynthesis of Gangliosides

• Biosynthesis is catalyzed by a series of
  glycotransferases
• Enzyme that acts as a catalyst for the transfer
  of a monosaccharide unit from an activated sugar
  phosphate.
• The pathway begins with transfer of galactosyl
  unit from UDP-Gal to form galacocerebroside to
  form ?(1-4) linkage
• Lactosyl ceramide - precursor for gangliosides
• GM2 formed by addition of NANA(sailic acid) from
  CMP-NANA to lactosyl ceramide ?(2-3) linkage

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Biosynthesis of Ganglioside

• Additions to GM3 of NANA and Gal from UDP-GalNac
  and UDP-Gal yield GM2 gangliosides.

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Biosynthesis of Gangliosides
1. Voet, D. Voet, J.G. Biochemistry, 3rd edition

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Treatments

• Enzyme replacement therapy
• Replace with synthetic enzyme
• Gene therapy
• Replace defective genes
• Substrate reduction therapy
• Bypass the defect so GM2 can be metabolized

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Conclusion

• Tay Sachs disease is autosomal recessive
  inheritance
• Occurs when there is a build up of gangliosides
  in the nerve cells of the brain
• It is a lipid storage disorder that results from
  the deficiency of hexosaminidase A
• Is a crippling and fatal disease
• ?-hexaminidase A gets degradated

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Conclusion

• GM2 ganglioside consists of NANA-Gal-Glc-Cer
• Biosynthesis is catalyzed by a series of
  glycotransferases
• GM2 activator protein helps GM2 recognize and
  cleave
• Several treatments but no cure