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Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human G M1 -Gangliosidosis.
- Source :
-
Journal of clinical medicine [J Clin Med] 2020 Apr 02; Vol. 9 (4). Date of Electronic Publication: 2020 Apr 02. - Publication Year :
- 2020
-
Abstract
- G <subscript>M1</subscript> -gangliosidosis is caused by a reduced activity of β-galactosidase ( Glb1 ), resulting in intralysosomal accumulations of G <subscript>M1</subscript> . The aim of this study was to reveal the pathogenic mechanisms of G <subscript>M1</subscript> -gangliosidosis in a new Glb1 knockout mouse model. Glb1 <superscript>-/-</superscript> 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 <superscript>-/-</superscript> 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 <subscript>M1</subscript> , G <subscript>A1</subscript> , sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1 <superscript>-/-</superscript> 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.
Details
- Language :
- English
- ISSN :
- 2077-0383
- Volume :
- 9
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of clinical medicine
- Publication Type :
- Academic Journal
- Accession number :
- 32252429
- Full Text :
- https://doi.org/10.3390/jcm9041004