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Open AccessArticle

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

1
Department of Pathology, University of Veterinary Medicine Hannover, D-30559 Hannover, Germany
2
Department of Physiological Chemistry, University of Veterinary Medicine Hannover, D-30559 Hannover, Germany
3
c/o Faculty of Veterinary Science, Prince of Sonkla University, 5 Karnjanavanich Rd., Hat Yai, Songkhla 90110, Thailand
4
Villa Metabolica, University of Mainz, Langenbeckstraße 2, D-55131 Mainz, Germany
5
Department for Physiology and Cell Biology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(4), 1004; https://doi.org/10.3390/jcm9041004
Received: 5 March 2020 / Revised: 29 March 2020 / Accepted: 30 March 2020 / Published: 2 April 2020
GM1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of GM1. The aim of this study was to reveal the pathogenic mechanisms of GM1-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 GM1, GA1, 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. View Full-Text
Keywords: astrogliosis; axonopathy; β-galactosidase deficiency; electrophysiology; GM1-gangliosidosis; knockout mouse model; lipid analysis; microgliosis; neuronal vacuolation astrogliosis; axonopathy; β-galactosidase deficiency; electrophysiology; GM1-gangliosidosis; knockout mouse model; lipid analysis; microgliosis; neuronal vacuolation
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MDPI and ACS Style

Eikelberg, D.; Lehmbecker, A.; Brogden, G.; Tongtako, W.; Hahn, K.; Habierski, A.; Hennermann, J.B.; Naim, H.Y.; Felmy, F.; Baumgärtner, W.; Gerhauser, I. Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis. J. Clin. Med. 2020, 9, 1004. https://doi.org/10.3390/jcm9041004

AMA Style

Eikelberg D, Lehmbecker A, Brogden G, Tongtako W, Hahn K, Habierski A, Hennermann JB, Naim HY, Felmy F, Baumgärtner W, Gerhauser I. Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis. Journal of Clinical Medicine. 2020; 9(4):1004. https://doi.org/10.3390/jcm9041004

Chicago/Turabian Style

Eikelberg, Deborah; Lehmbecker, Annika; Brogden, Graham; Tongtako, Witchaya; Hahn, Kerstin; Habierski, Andre; Hennermann, Julia B.; Naim, Hassan Y.; Felmy, Felix; Baumgärtner, Wolfgang; Gerhauser, Ingo. 2020. "Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis" J. Clin. Med. 9, no. 4: 1004. https://doi.org/10.3390/jcm9041004

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