β-hexosaminidase activity and the effects of ganglioside storage on neuronal function were examined in a German shorthair pointer (GSHP) with progressive neurodegenerative signs. Morphologic evidence of neuronal storage and massive accumulation of GM2 ganglioside were present. β-hexosaminidase activity in plasma, liver, kidney, and brain, assayed with use of unsulfated fluorogenic substrates, was normal. There was no pathologic accumulation or aberrant localization of phosphorylated neurofilaments in neurons. Activity of cortical neurotransmitter synthesizing enzymes, choline acetyltransferase, and glutamate decarboxylase was unaffected. Ligand binding to carrier sites for choline high affinity uptake identified with [3H]hemicholinium-3 was increased, whereas post-synaptic binding to muscarinic cholinergic ([3H]QNB) and gamma-aminobutryic acid receptors ([3H]muscimol) was reduced.
References
1.
BeaumontKChiltonWSYamamuraHIEnnaSJ:
Muscimol binding in rat brain: association with synaptic GABA receptors.
Brain Res148:
153–162,
1978
2.
BernheimerHKarbeE:
Morphologische und neurochemische Untersuchungen von 2 Formen der amaurotischen Idiote des Hundes: nachweis einer GM2-Gangliosidose.
Acta Neuropathol (Berl)16:
243–261,
1970
3.
BullGOderfeld-NowakB:
Standardization of a radiochemical assay of choline acetyltransferase and a study of the activation of the enzyme in rabbit brain.
J Neurochem18:
935–941,
1971
4.
ConzelmannEKytziaHNavonR:
Ganglioside GM2 N-acetyl-b-D-galactosaminidase activity in cultured fibroblasts of late-infantile and adult GM2 gangliosidosis patients and of healthy probands with low hexosaminidase level.
Am J Hum Genet35:
900–913,
1983
5.
ConzelmannESandhoffK:
AB variant of infantile GM2-gangliosidosis: deficiency of a factor necessary for stimulation of hexosaminidase A-catalyzed degradation of ganglioside GM2 and glycolipid GA2.
Proc Natl Acad Sci USA75:
3979–3983,
1978
6.
CorkLCMunnellJFLorenzMDMurphyJV:
GM2 ganglioside lysosomal storage disease in cats with b-hexosaminidase deficiency.
Science196:
1014–1017,
1977
7.
CorkLCSternbergerNHSternbergerLACasanovaMFStrubleRGPriceDL:
Phosphorylated neurofilament antigens in neurofibrillary tangles in Alzheimer's disease.
J Neuropathol Exp Neurol45:
56–64,
1986
8.
CorkLCTroncosoJCKlavanoGGJohnsonESSternbergerLASternbergerNHPriceDL:
Neurofilamentous pathology in motor neurons in spontaneously occurring animal disorders.
J Neuropathol Exp Neurol47:
420–431,
1988
9.
CummingsJFWoodPAWalkleySUdeLahuntaADeForestME:
GM2 gangliosidosis in a Japanese spaniel.
Acta Neuropathol (Berl)67:
247–253,
1985
10.
FacciLLeonAToffanoGSonninoSGhidoniRTettamantiG:
Promotion of neuritogenesis in mouse neuroblastoma cells by exogenous gangliosides. Relationship between the effect and the cell association of ganglioside GM1.
J Neurochem42:
299–305,
1984
GoebelHH:
Morphology of the gangliosidoses.
Neuropediatrics15
(Suppl):
97–106,
1984
13.
HechtmanPGordonBAKinNMK:
Deficiency of the hexosaminidase activator protein in a case of GM2-gangliosidosis, variant AB.
Pediatr Res16:
217–222,
1982
14.
HirabayashiYLiYTLeeS:
The protein activator specific for the enzymic, hydrolysis of GM2 in normal human brain and brains of three types of GM2 gangliosidosis.
J Neurochem40:
168–175,
1983
15.
IshikawaYLiS:
Biochemical basis of type AB GM2 gangliosidosis in a Japanese spaniel.
J Neurochem4:
860–864,
1987
16.
KarbeESchieferB:
Familial amaurotic idiocy in male German shorthair pointers.
Pathol Vet4:
223–232,
1967
17.
KosankeSDPierceKRBayWW:
Clinical and biochemical abnormalities in porcine GM2-gangliosidosis.
Vet Pathol15:
685–699,
1978
18.
KytziaH:
Variant of GM2-gangliosidosis with hexosaminidase A having a severely changed substrate specificity.
EMBO J2:
1201–1205,
1983
19.
KytziaH:
Evidence for two different active sites on human b-hexosaminidase A.
J Biol Chem260:
7568–7572,
1985
20.
LedeenRW:
Structure and distribution of gangliosides.
In:
Complex Carbohydrates of Nervous Tissue,
MargolisRUMargolisRK,
pp. 1–22.
Plenum Press,
New York,
1979
21.
LowryOHRosebroughNJFarrALRandallRJ:
Protein measurement with the folin phenol reagent.
J Biol Chem193:
265–275,
1951
22.
McGrathJTKellyAMSteinbergSA:
Cerebral lipidosis in the dog.
J Neuropathol Exp Neurol27:
141,
1968
23.
MiyazakiKOkamuraNKishimotoYLeeYC:
Determination of gangliosides as 2,4-dinitrophenylhydrazides by high-performance liquid chromatography.
Biochem J235:
755–761,
1986
24.
NagataYAndoMIwataMHaraATaketomiT:
Effect of exogenous gangliosides on amino acid uptake and Na+, K+-ATPase activity in superior cervical and nodose ganglia of rats.
J Neurochem49:
201–207,
1987
25.
NeuweltEAJohnsonWGBlankNKPagelMAMasienC:
Characterization of a new model of GM2-gangliosidosis (Sandhoff's disease) in Korat cats.
J Clin Invest76:
482–490,
1985
26.
PierceKRKosankeSDBayWWBridgesCH:
GM2-gangliosidosis: porcine cerebrospinal lipodystrophy.
Am J Pathol83:
419–421,
1976
27.
PurpuraDPBakerHJ:
Meganeurites and other aberrant processes of neurons in feline GM1 gangliosidosis: a Golgi study.
Brain Res143:
13–26,
1978
28.
PurpuraDPSuzukiK:
Distortion of neuronal geometry and formation of aberrant synapses in neuronal Storage disease.
Brain Res116:
1–21,
1976
29.
RosenfeldJDormanMEGriffinJWGoldBGSternbergerLASternbergerNHPriceDL:
Distribution of neurofilament antigens after axonal injury.
J Neuropathol Exp Neurol46:
269–282,
1987
30.
SandbergKCoyleJT:
Characterization of [3H]hemicholinium-3 binding associated with neuronal choline uptake sites in rat brain membranes.
Brain Res348:
321–330,
1985
31.
SandhoffKHarzerKWassleWJatzkewitzH:
Enzyme alterations and lipid storage in three variants of Tay-Sachs disease.
J Neurochem18:
2469–2489,
1971
32.
SchulteFJ:
Clinical course of GM2 gangliosidosis: a correlative attempt.
Neuropediatrics15:
66–70,
1984
33.
SingerHSCoyleJTWeaverDLKawamuraNBakerHJ:
Neurotransmitter chemistry in feline GM1 gangliosidosis: a model for human ganglioside storage disease.
Ann Neurol12:
37–41,
1982
34.
SingerHSTiemeyerMSlesingerPASinnottML:
Inactivation of GM1-ganglioside b-galactosidase by a specific inhibitor: a model for ganglioside storage disease.
Ann Neurol21:
497–503,
1987
35.
SkrivanekJALedeenRWMargolisRUMargolisRK:
Gangliosides associated with microsomal subfractions of brain: comparison with synaptic plasma membranes.
J Neurobiol13:
95–106,
1982
36.
SonderfeldSBrendlerSSandhoffKGaljaardHHoogeveenAT:
Genetic complementation in somatic cell hybrids of four variants of infantile GM2 gangliosidosis.
Hum Genet71:
196–200,
1985
37.
SternbergerLASternbergerNH:
Monoclonal antibodies distinguish phosphorylated and nonphosphorylated forms of neurofilaments in situ.
Proc Natl Acad Sci USA80:
6126–6130,
1983
38.
TroncosoJCSternbergerLASternbergerNHCorkLC:
Phosphorylated neurofilaments in neurons in aluminum intoxication.
Ann Neurol18:
149–150,
1985
39.
WalkleySUWorzelmannSPurpuraDP:
Ultrastructure of neurites and meganeurites of cortical pyramidal neurons in feline gangliosidosis as revealed by the combined Golgi-EM technique.
Brain Res211:
393–398,
1981
40.
WileyCALoveSSkoglundRRLampertPW:
Infantile neurodegenerative disease with neuronal accumulation of phosphorylated neurofilaments.
Acta Neuropathol (Berl)72:
369–376,
1987
41.
WilsonSHSchrierRKFarberJLThompsonEJRosenbergRNBlumeAJNirenbergMW:
Markers for gene expression in cultured cells from the nervous system.
J Biol Chem247:
3159–3169,
1972
42.
WoodPAMcBrideMRBakerHJChristianST:
Fluorescence polarization analysis, lipid composition, and Na+, K+-ATPase kinetics of synaptosomal membranes in feline GM1 and GM2 gangliosidosis.
J Neurochem44:
947–956,
1985
43.
YamamuraHSnyderS:
Muscarinic cholinergic binding in rat brain.
Proc Natl Acad Sci USA71:
1725–1729,
1977
