Abstract
The G(M2) activator deficiency (also known as the AB variant), Tay- Sachs disease, and Sandhoff disease are the major forms of the G(M2) gangliosidoses, disorders caused by defective degradation of G(M2) ganglioside. Tay-Sachs and Sandhoff diseases are caused by mutations in the genes (HEXA and HEXB) encoding the subunits of β-hexosaminidase A. The G(M2) activator deficiency is caused by mutations in the GM2A gene encoding the G(M2) activator protein. For degradation of G(M2) ganglioside by β- hexosamindase A, the G(M2) activator protein must participate by forming a soluble complex with the ganglioside. In each of the disorders, G(M2) ganglioside and related lipids accumulate to pathologic levels in neuronal lysosomes, resulting in clinically similar disorders with an onset in the first year of life, progressive neurodegeneration, and death by early childhood. We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes. The Hexa -/- mice were asymptomatic whereas the Hexb -/- mice were severely affected. Through gene disruption in embryonic stem cells we now have established a mouse model of the G(M2) activator deficiency that manifests an intermediate phenotype. The Gm2a -/- mice demonstrated neuronal storage but only in restricted regions of the brain (piriform, entorhinal cortex, amygdala, and hypothalamic nuclei) reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in the Gm2a -/- mice consisted of G(M2) with a low amount of G(A2). The results demonstrate that the activator protein is required for G(M2) degradation and also may indicate a role for the G(M2) activator in G(A2) degradation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 8138-8143 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 94 |
| Issue number | 15 |
| DOIs | |
| State | Published - 1997 |
| Externally published | Yes |
Fingerprint
Keywords
- Animal model
- G(M2) gangliosidosis
- Gene targeting
- Lysosomal storage disease
ASJC Scopus subject areas
- General
- Genetics
Cite this
Mouse model of G(M2) activator deficiency manifests cerebellar pathology and motor impairment. / Liu, Y.; Hoffmann, A.; Grinberg, A.; Westphal, H.; McDonald, M. P.; Miller, K. M.; Crawley, Jacqueline; Sandhoff, K.; Suzuki, K.; Proia, R. L.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 15, 1997, p. 8138-8143.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mouse model of G(M2) activator deficiency manifests cerebellar pathology and motor impairment
AU - Liu, Y.
AU - Hoffmann, A.
AU - Grinberg, A.
AU - Westphal, H.
AU - McDonald, M. P.
AU - Miller, K. M.
AU - Crawley, Jacqueline
AU - Sandhoff, K.
AU - Suzuki, K.
AU - Proia, R. L.
PY - 1997
Y1 - 1997
N2 - The G(M2) activator deficiency (also known as the AB variant), Tay- Sachs disease, and Sandhoff disease are the major forms of the G(M2) gangliosidoses, disorders caused by defective degradation of G(M2) ganglioside. Tay-Sachs and Sandhoff diseases are caused by mutations in the genes (HEXA and HEXB) encoding the subunits of β-hexosaminidase A. The G(M2) activator deficiency is caused by mutations in the GM2A gene encoding the G(M2) activator protein. For degradation of G(M2) ganglioside by β- hexosamindase A, the G(M2) activator protein must participate by forming a soluble complex with the ganglioside. In each of the disorders, G(M2) ganglioside and related lipids accumulate to pathologic levels in neuronal lysosomes, resulting in clinically similar disorders with an onset in the first year of life, progressive neurodegeneration, and death by early childhood. We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes. The Hexa -/- mice were asymptomatic whereas the Hexb -/- mice were severely affected. Through gene disruption in embryonic stem cells we now have established a mouse model of the G(M2) activator deficiency that manifests an intermediate phenotype. The Gm2a -/- mice demonstrated neuronal storage but only in restricted regions of the brain (piriform, entorhinal cortex, amygdala, and hypothalamic nuclei) reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in the Gm2a -/- mice consisted of G(M2) with a low amount of G(A2). The results demonstrate that the activator protein is required for G(M2) degradation and also may indicate a role for the G(M2) activator in G(A2) degradation.
AB - The G(M2) activator deficiency (also known as the AB variant), Tay- Sachs disease, and Sandhoff disease are the major forms of the G(M2) gangliosidoses, disorders caused by defective degradation of G(M2) ganglioside. Tay-Sachs and Sandhoff diseases are caused by mutations in the genes (HEXA and HEXB) encoding the subunits of β-hexosaminidase A. The G(M2) activator deficiency is caused by mutations in the GM2A gene encoding the G(M2) activator protein. For degradation of G(M2) ganglioside by β- hexosamindase A, the G(M2) activator protein must participate by forming a soluble complex with the ganglioside. In each of the disorders, G(M2) ganglioside and related lipids accumulate to pathologic levels in neuronal lysosomes, resulting in clinically similar disorders with an onset in the first year of life, progressive neurodegeneration, and death by early childhood. We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes. The Hexa -/- mice were asymptomatic whereas the Hexb -/- mice were severely affected. Through gene disruption in embryonic stem cells we now have established a mouse model of the G(M2) activator deficiency that manifests an intermediate phenotype. The Gm2a -/- mice demonstrated neuronal storage but only in restricted regions of the brain (piriform, entorhinal cortex, amygdala, and hypothalamic nuclei) reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in the Gm2a -/- mice consisted of G(M2) with a low amount of G(A2). The results demonstrate that the activator protein is required for G(M2) degradation and also may indicate a role for the G(M2) activator in G(A2) degradation.
KW - Animal model
KW - G(M2) gangliosidosis
KW - Gene targeting
KW - Lysosomal storage disease
UR - http://www.scopus.com/inward/record.url?scp=0030610850&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030610850&partnerID=8YFLogxK
U2 - 10.1073/pnas.94.15.8138
DO - 10.1073/pnas.94.15.8138
M3 - Article
C2 - 9223328
AN - SCOPUS:0030610850
VL - 94
SP - 8138
EP - 8143
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 15
ER -