Abnormally accumulated GM2 ganglioside contributes to skeletal deformity in Tay-Sachs mice.

Autor: Demir SA; Izmir Institute of Technology, IYTEDEHAM, Urla, Izmir, Turkey., Seyrantepe V; Izmir Institute of Technology, IYTEDEHAM, Urla, Izmir, Turkey. volkanseyrantepe@iyte.edu.tr.; Department of Molecular Biology and Genetics, Izmir Institute of Technology, Urla, Izmir, Turkey. volkanseyrantepe@iyte.edu.tr.
Jazyk: angličtina
Zdroj: Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2024 Dec; Vol. 102 (12), pp. 1517-1526. Date of Electronic Publication: 2024 Nov 08.
DOI: 10.1007/s00109-024-02498-6
Abstrakt: Tay-Sachs Disease is a rare lysosomal storage disorder caused by mutations in the HEXA gene, responsible for the degradation of ganglioside GM2. In addition to progressive neurodegeneration, Tay-Sachs patients display bone anomalies, including kyphosis. Tay-Sachs disease mouse model (Hexa-/-Neu3-/-) shows both neuropathological and clinical abnormalities of the infantile-onset disease phenotype. In this study, we investigated the effects of GM2 accumulation on bone remodeling activity. Here, we evaluated the bone phenotype of 5-month-old Hexa-/-Neu3-/- mice with age-matched control groups using gene expression analysis, bone plasma biomarker analysis, and micro-computed tomography. We demonstrated lower plasma alkaline phosphatase activity and calcium levels with increased tartrate-resistant acid phosphatase levels, indicating reduced bone remodeling activity in mice. Consistently, gene expression analysis confirmed osteoblast reduction and osteoclast induction in the femur of mice. Micro-computed tomography and analysis show reduced trabecular bone volume, mineral density, number, and thickness in Hexa-/-Neu3-/- mice. In conclusion, we demonstrated that abnormal GM2 ganglioside accumulation significantly triggers skeletal abnormality in Tay-Sachs mice. We suggest that further investigation of the molecular basis of bone structure anomalies is necessary to elucidate new therapeutic targets that prevent the progression of bone symptoms and improve the life standards of Tay-Sachs patients. KEY MESSAGES: We detected the markers of bone loss-associated disorders such as osteopenia and osteoporosis in the Tay-Sachs disease mice model Hexa-/-Neu3-/-. We also demonstrated for the first time there is an increase in trabecular spacing and a reduction in trabecular thickness and number indicating skeletal abnormalities in mice model using micro-CT analysis.
Competing Interests: Declarations. Ethics approval: The animal study was reviewed and approved by IYTEHADYEK. Conflict of interest: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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