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Investigating the therapeutic effects of simvastatin on a mouse model of Rett syndrome
- Publication Year :
- 2024
-
Abstract
- Rett syndrome (RTT) is a progressive neurodevelopmental disorder without an available cure. It is a rare disease but is known as one of the most common causes of intellectual disabilities and motor dysfunction in females. Approximately 90-95% of RTT cases result from loss-of-function mutations in the X-linked gene called the Methyl-CpG binding protein 2 (MECP2). MeCP2-T158M is the most common missense mutation found in patients, accounting for about 12% of RTT cases. Interestingly, it was reported that increasing MeCP2-T158M expression improved RTT-like phenotypes in both T158M male and female mice in vivo. For over ten years, researchers have been interested in statins, a family of drugs used to lower plasma LDL-cholesterol, as a potential treatment for RTT due to impaired cholesterol metabolism associated with the syndrome. In the statin family, simvastatin has the highest lipophilicity and can effectively cross the blood-brain barrier to enhance its bioavailability in the brain. Therefore, in this research thesis, I hypothesize that increased translation caused by simvastatin will increase the levels of MeCP2 and MeCP2E1 in the brain of Mecp2T158M/y mice and rescue altered levels of other RTT-related proteins. Additionally, simvastatin improves RTT-like phenotypes in Mecp2T158M/y mice. I address my hypotheses through two research aims: determine the molecular effects of simvastatin at the protein level in a brain-region-dependent manner and examine the therapeutic effects of simvastatin on RTT-like phenotypes in the Mecp2T158M/y mouse model. The results showed that at the protein level, simvastatin significantly increased the levels of pS6 Ser235/236 and pS6 Ser240/244 in the cerebral cortex of T158M male mice, suggesting the molecular effects of simvastatin on increasing translation. Furthermore, preliminary data revealed a trend of improving RTT-like phenotypes in a dose-dependent manner with simvastatin treatment. Nevertheless, simvastatin did not rescue reduc
Details
- Database :
- OAIster
- Notes :
- English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1442955391
- Document Type :
- Electronic Resource