| First Author | Raha S | Year | 2023 |
| Journal | Cells | Volume | 12 |
| Issue | 24 | PubMed ID | 38132111 |
| Mgi Jnum | J:353489 | Mgi Id | MGI:7568135 |
| Doi | 10.3390/cells12242791 | Citation | Raha S, et al. (2023) Lipid-Lowering Drug Gemfibrozil Protects Mice from Tay-Sachs Disease via Peroxisome Proliferator-Activated Receptor alpha. Cells 12(24) |
| abstractText | Tay-Sachs disease (TSD) is a progressive heritable neurodegenerative disorder characterized by the deficiency of the lysosomal beta-hexosaminidase enzyme (Hex(-/-)) and the storage of GM2 ganglioside, as well as other related glycoconjugates. Along with motor difficulties, TSD patients also manifest a gradual loss of skills and behavioral problems, followed by early death. Unfortunately, there is no cure for TSD; however, research on treatments and therapeutic approaches is ongoing. This study underlines the importance of gemfibrozil (GFB), an FDA-approved lipid-lowering drug, in inhibiting the disease process in a transgenic mouse model of Tay-Sachs. Oral administration of GFB significantly suppressed glial activation and inflammation, while also reducing the accumulation of GM2 gangliosides/glycoconjugates in the motor cortex of Tay-Sachs mice. Furthermore, oral GFB improved behavioral performance and increased the life expectancy of Tay-Sachs mice. While investigating the mechanism, we found that oral administration of GFB increased the level of peroxisome proliferator-activated receptor alpha (PPARalpha) in the brain of Tay-Sachs mice, and that GFB remained unable to reduce glycoconjugates and improve behavior and survival in Tay-Sachs mice lacking PPARalpha. Our results indicate a beneficial function of GFB that employs a PPARalpha-dependent mechanism to halt the progression of TSD and increase longevity in Tay-Sachs mice. |
