| Summary: | G<sub>M1</sub>-gangliosidosis is caused by a reduced activity of β-galactosidase (<i>Glb1</i>), resulting in intralysosomal accumulations of G<sub>M1</sub>. The aim of this study was to reveal the pathogenic mechanisms of G<sub>M1</sub>-gangliosidosis in a new <i>Glb1</i> knockout mouse model. <i>Glb1</i><sup>−/−</sup> 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. <i>Glb1</i><sup>−/−</sup> 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<sub>M1</sub>, G<sub>A1</sub>, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current <i>Glb1</i><sup>−/−</sup> 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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