Lithium treatment rescues dysfunctional autophagy in the cell models of Tay-Sachs disease.

Autor: Basirli H; İzmir Institute of Technology, Department of Molecular Biology and Genetics, İzmir, Turkey., Can M; İzmir Institute of Technology, Department of Molecular Biology and Genetics, İzmir, Turkey., Sengul T; İzmir Institute of Technology, Department of Molecular Biology and Genetics, İzmir, Turkey., Seyrantepe V; İzmir Institute of Technology, Department of Molecular Biology and Genetics, İzmir, Turkey; İzmir Institute of Technology, IYTEDEHAM, İzmir, Turkey. Electronic address: volkanseyrantepe@iyte.edu.tr.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2024 Mar; Vol. 141 (3), pp. 108140. Date of Electronic Publication: 2024 Jan 11.
DOI: 10.1016/j.ymgme.2024.108140
Abstrakt: Tay-Sachs disease is a rare lysosomal storage disorder (LSD) caused by a mutation in the HexA gene coding β-hexosaminidase A enzyme. The disruption of the HexA gene causes the accumulation of GM2 ganglioside resulting in progressive neurodegeneration in humans. Surprisingly, Hexa-/- mice did not show neurological phenotypes. Our group recently generated a murine model of Tay-Sachs disease exhibiting excessive GM2 accumulation and severe neuropathological abnormalities mimicking Tay-Sachs patients. Previously, we reported impaired autophagic flux in the brain of Hexa/-Neu3-/- mice. However, regulation of autophagic flux using inducers has not been clarified in Tay-Sachs disease cells. Here, we evaluated the effects of lithium treatment on dysfunctional autophagic flux using LC3 and p62 in the fibroblast and neuroglia of Hexa-/-Neu3-/- mice and Tay-Sachs patients. We discovered the clearance of accumulating autophagosomes, aggregate-prone metabolites, and GM2 ganglioside under lithium-induced conditions. Our data suggest that targeting autophagic flux with an autophagy inducer might be a rational therapeutic strategy for the treatment of Tay-Sachs disease.
Competing Interests: Declaration of competing interest None
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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