Journal
JOURNAL OF CLINICAL MEDICINE
Volume 9, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/jcm9041004
Keywords
astrogliosis; axonopathy; beta-galactosidase deficiency; electrophysiology; G(M1)-gangliosidosis; knockout mouse model; lipid analysis; microgliosis; neuronal vacuolation
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Funding
- German Research Foundation (DFG) [BA815/12-1]
- Deutsche Forschungsgemeinschaft
- University of Veterinary Medicine Hannover, Foundation
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G(M1)-gangliosidosis is caused by a reduced activity of beta-galactosidase (Glb1), resulting in intralysosomal accumulations of G(M1). The aim of this study was to reveal the pathogenic mechanisms of G(M1)-gangliosidosis in a new Glb1 knockout mouse model. Glb1(-/-) mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1(-/-) mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material G(M1), G(A1), sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1(-/-) mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon-glial interactions and therapy trials of lysosomal storage diseases.
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