Neurotransmitter chemistry in feline GM₁ gangliosidosis: A model for human ganglioside storage disease

Abstract

Assays for synaptosomal high-affinity uptake activity (glutamate, y-aminobutyric acid, norepinephrine), neurotransmitter synthesizing enzymes (choline acetyltransferase, glutamate decarboxylase, tyrosine hydroxylase), and endogenous neurotransmitters were performed in cats with advanced inherited GM, gangliosidosis. A significant reduction in uptake activity, ranging from 24 to 77% of control, was demonstrated in motor, occipital, and cerebellar brain regions. This reduction was unassociated with comparable alterations in neurotransmitter levels or synthesizing enzyme activity. We hypothesize that the defect of neurotransmitter inactivation is part of an overall abnormality of synaptic membrane function that could contribute to the neurological symptoms seen in the hereditary gangliosidoses.

Metabolism of cerebroside sulfate and subcellular distribution of its metabolites in cultured skin fibroblasts from controls, metachromatic leukodystrophy, and globoid cell leukodystrophy.

“…Recent morphological studies of neurons from humans (7), cats (8), and dogs (9) with gangliosidoses have shown meganeurities, inappropriate proliferation of secondary neurites, aberrant synaptogenesis, somatic swelling, and abnormal somatic processes. Biochemically, impaired neurotransmitter metabolism was suggested in cerebral cortical and cerebellar synaptosomes from cats with GM, gangliosidosis (10) and increased amount of ganglioside in synaptosomal membranes from feline GM, and GM2 gangliosidosis was presented (11). These studies suggested that altered membrane structure could be one of causes of neuronal dysfunction.…”

Increased Acetylcholine Synthesis and Release in Brains of Cats with GM1 Gangliosidosis

“…46, (1986. synaptosomal membranes, including increased total gangliosides, cholesterol, and phospholipids (Wood et al, 1985); (b) reduced fluidity ofsynaptosomal membranes which correlates with the onset of neurological disease (Wood et al, 1985); (c) neuronal loss does not occur until terminal stages of the illness (Walkley, 1981); (d) significant morphological alterations occur early in the disease, including prominent expansions (meganeurites) between the soma and the initial axon segment, inappropriate proliferation of secondary neurites, aberrant synaptogenesis, somatic swelling, and abnormal somatic processes (Purpura and Baker, 1977;Walkley et al, 1981); (e) no defects in electrogenic properties ; and (0 high-affinity uptake of glutamate, y-aminobutyrate and norepinephrine are reduced in synaptosomes prepared from the cerebral cortex and cerebellum (Singer et al, 1981). The latter investigation appears t o be the only report of neurotransmitter function in feline G,, gangliosidosis.…”

Neurotransmitter glutamate: its clinical importance

“…Reduced uptake and inactivation of transmitter glutamate has been related to an altered synaptic membrane ganglioside function in feline GM-1 gangliosidosis (181).…”