myelin-basic-protein and Gangliosidosis--GM1

The present study investigated cerebrospinal fluid (CSF) biomarkers for estimating degeneration of the central nervous system (CNS) in experimental dogs with GM1 gangliosidosis and preliminarily evaluated the efficacy of long-term glucocorticoid therapy for GM1 gangliosidosis using the biomarkers identified here. GM1 gangliosidosis, a lysosomal storage disease that affects the brain and multiple systemic organs, is due to an autosomal recessively inherited deficiency of acid beta-galactosidase activity. Pathogenesis of GM1 gangliosidosis may include neuronal apoptosis and abnormal axoplasmic transport and inflammatory response, which are perhaps consequent to massive neuronal storage of GM1 ganglioside. In the present study, we assessed some possible CSF biomarkers, such as GM1 ganglioside, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and myelin basic protein (MBP). Periodic studies demonstrated that GM1 ganglioside concentration, activities of AST and LDH, and concentrations of NSE and MBP in CSF were significantly higher in dogs with GM1 gangliosidosis than those in control dogs, and their changes were well related with the months of age and clinical course. In conclusion, GM1 ganglioside, AST, LDH, NSE and MBP could be utilized as CSF biomarkers showing CNS degeneration in dogs with GM1 gangliosidosis to evaluate the efficacy of novel therapies proposed for this disease. In addition, we preliminarily treated an affected dog with long-term oral administration of prednisolone and evaluated the efficacy of this therapeutic trial using CSF biomarkers determined in the present study. However, this treatment did not change either the clinical course or the CSF biomarkers of the affected dog, suggesting that glucocorticoid therapy would not be effective for treating GM1 gangliosidosis.

Topics: Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Biomarkers; Brain; Cerebrospinal Fluid Proteins; Disease Models, Animal; Dogs; G(M1) Ganglioside; Gangliosidosis, GM1; L-Lactate Dehydrogenase; Myelin Basic Protein; Nerve Degeneration; Phosphopyruvate Hydratase; Predictive Value of Tests; Prednisolone; Treatment Outcome; Up-Regulation

A myelin deficit in the cerebral white matter in infantile GM1 gangliosidosis is well established. Some have proposed this deficit to be secondary to axonal loss, while others argue for delayed or arrested myelination. We compared the frontal white and gray matter of two infants with GM1 gangliosidosis with four age-matched controls, using light microscopy with a quantitative analysis, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL), and electron microscopy (EM). In the GM1 cases, we found a marked decrease in the number of oligodendrocytes (85% in case 1 and 50% in case 2) and myelin sheaths (80% and 40%), with a mild decrease in axons (20% and 10%). Ultrastructurally, some naked axons and dilated cisterns of rough endoplasmic reticulum (RER) in oligodendrocytes were observed. There was no appreciable storage in remaining oligodendrocytes, nor obvious neocortical neuronal loss. An immunohistochemical decrease in proteolipid protein (PLP) and a more profound deficiency of myelin basic protein (MBP) indicate that this lesion is not simply the result of a delay or arrest in myelination and suggests a "dying-back" oligopathy. TUNEL-positive oligodendrocytes correlated with activated caspase-3 immunoreactivity. Amyloid precursor protein (APP)-immunoreactive aggregates were observed in proximal axons and meganeurites as well as in white matter axons. These data suggest that the myelin deficit results from a loss of oligodendrocytes and abnormal axoplasmic transport, perhaps consequent to massive neuronal storage of GM1.

Topics: Amyloid beta-Protein Precursor; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Apoptosis; Axons; Brain; Carbonic Anhydrases; Case-Control Studies; Cell Count; DNA-Binding Proteins; Female; Gangliosidosis, GM1; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Infant; Ki-67 Antigen; Male; Microscopy, Electron; Myelin Basic Protein; Oligodendroglia; Receptors, Platelet-Derived Growth Factor; Subacute Sclerosing Panencephalitis; Transcription Factors