Skip to main content
SpringerLink
Log in

Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease

  • Regular Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

A murine model of Tay-Sachs disease, the prototype of the GM2 gangliosidoses, was produced through the targeted disruption of the Hexa gene encoding the subunit of α-hexosaminidase A. The mice were completely devoid of β-hexosaminidase A activity and accumulated GM2 ganglioside in the CNS in an age-dependent manner. Neurons with membranous cytoplasmic bodies (MCBs), identical to those described in Tay-Sachs disease, were identified in the brain of these mice. The neurons with MCBs were periodic acid-Schiff-positive on frozen sections and immunostained with anti-GM2 ganglioside antibody. However, unlike Tay-Sachs disease in which neurons throughout the brain are affected, the localization of storage neurons in these mice appeared to be limited to certain regions, i.e., cerebral cortex, the hippocampus, amygdala, hypothalamus, mammillary nucleus, etc. Storage neurons were absent in the olfactory bulb, cerebellar cortex and spinal anterior horns. The difference in the distribution of storage neurons suggests a difference of ganglioside metabolism between humans and mice. This model is useful for the study of the pathogenic mechanisms of neuronal storage in Tay-Sachs disease and for the evaluation of therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Adachi M, Schneck L, Volk BW (1974) Ultrastructural studies of eight cases of fetal Tay-Sachs disease. Lab Invest 30: 102–112

    Google Scholar 

  2. Burg J, Banerjee A, Conzelmann E, Sandhoff K (1983) Activating proteins for ganglioside GM2 degradation by β-hexosaminidase isoenzymes in tissue extracts from different species. Hoppe-Seyler's Z Physiol Chem 364: 821–829

    Google Scholar 

  3. Carpenter MB, Sutin J (1983) Human neuroanatomy. Williams & Wilkins, Baltimore

    Google Scholar 

  4. Cork LC, Munnell JF, Lorenz MD (1977) GM2 ganglioside lysosomal storage disease in cats with β-hexosaminidase deficiency. Science 196: 1014–1017

    Google Scholar 

  5. Dobrenis K, Joseph A, Rattazzi MC (1992) Neuronal lysosomal enzyme replacement using fragment C of tetanus toxin. Proc Natl Acad Sci USA 89: 2297–2301

    Google Scholar 

  6. Goebel HH (1984) Morphology of gangliosidoses. Neuropediatrics 15 [Suppl]: 97–106

    Google Scholar 

  7. Karabelas AB, Walkley SU (1985) Altered patterns of evoked synaptic activity in cortical pyramidal neurons in feline ganglioside storage disease. Brain Res 339: 329–336

    Google Scholar 

  8. Mugnaini E, Oertel WH (1985) An atlas of the distribution of GABAergic neurons and terminals in the rat CNS as revealed by GAD immunohistochemistry. In: Bjorklund A, Hokfelt T (eds) Handbook of chemical neuroanatomy, vol 4. GABA and neuropeptides in the CNS. Elsevier, Amsterdam, pp 436–608

    Google Scholar 

  9. Muldoon LL, Neuwelt EA, Page MA, Weiss DL (1994) Characterization of the molecular defect in a feline model for type II GM2-gangliosidosis (Sandhoff disease). Am J Pathol 144: 1109–1118

    Google Scholar 

  10. Purpura DP, Suzuki K (1976) Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage diseases. Brain Res 116: 1–21

    Google Scholar 

  11. Sandhoff K, Conzelmann E, Neufeld EF, Kaback MM, Suzuki K (1989) The GM2 gangliosidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 1807–1839

    Google Scholar 

  12. Singer HS, Coyle JT, Weaver DL, Kawamura N, Baker HJ (1982) Neurotransmitter chemistry in feline GM1 gangliosidosis: a model for human ganglioside storage disease. Ann Neurol 12: 37–41

    Google Scholar 

  13. Suhr ST, Gage FH (1993) Gene therapy for neurologic disease. Arch Neurol 50: 1252–1268

    Google Scholar 

  14. Suzuki K (1991) Neuropathology of late onset gangliosidoses. A review. Dev Neurosci 13: 205–210

    Google Scholar 

  15. Walkley SU, Baker HJ, Rattazzi MC, Haskins ME, Wu JY (1991) Neuroaxonal dystrophy in neuronal storage disorders: evidence for major GABAergic neuron involvement. J Neurol Sci 104: 1–8

    Google Scholar 

  16. Yamanaka S, Johnson MD, Grinberg A, et al (1994) Targeted disruption of the Hexa gene results in mice with biochemical and pathologic features of Tay-Sachs disease. Proc Natl Acad Sci USA 91: 9975–9979

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, CB 7525, University of North Carolina at Chapel Hill, 27599-7525, Chapel Hill, NC, USA

    Masako Taniike, Clarita Langaman & Kinuko Suzuki

  2. Brain and Development Research Center, University of North Carolina at Chapel Hill, 27599-7525, Chapel Hill, NC, USA

    Teresa Bone-Turrentine & Kinuko Suzuki

  3. Section on Biochemical Genetics, Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 20892, Bethesda, MD, USA

    Shoji Yamanaka & Richard L. Proia

Authors
  1. Masako Taniike
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shoji Yamanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard L. Proia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Clarita Langaman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Teresa Bone-Turrentine
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kinuko Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taniike, M., Yamanaka, S., Proia, R.L. et al. Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease. Acta Neuropathol 89, 296–304 (1995). https://doi.org/10.1007/BF00309622

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00309622

Key words

Search

Navigation