Investigating the therapeutic effects of simvastatin on a mouse model of Rett syndrome
| dc.contributor.author | Vuu, Yen My | |
| dc.contributor.examiningcommittee | Doble, Brad (Biochemistry and Medical Genetics) | |
| dc.contributor.examiningcommittee | Marcogliese, Paul (Biochemistry and Medical Genetics) | |
| dc.contributor.supervisor | Rastegar, Mojgan | |
| dc.date.accessioned | 2024-03-19T20:10:34Z | |
| dc.date.available | 2024-03-19T20:10:34Z | |
| dc.date.issued | 2024-03-15 | |
| dc.date.submitted | 2024-03-15T22:29:47Z | en_US |
| dc.degree.discipline | Biochemistry and Medical Genetics | en_US |
| dc.degree.level | Master of Science (M.Sc.) | |
| dc.description.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 reduced levels of MeCP2 and MeCP2E1 in the brain of T158M male mice and altered levels of other RTT-related proteins such as SNAP25, PSD95 and Tau. Unexpectedly, simvastatin treatment may cause unexpected neuronal cell death. Collectively, further studies are needed to address the molecular impacts of simvastatin in the brain and the phenotypic outcomes at different doses. | |
| dc.description.note | May 2024 | |
| dc.identifier.uri | http://hdl.handle.net/1993/38060 | |
| dc.language.iso | eng | |
| dc.rights | open access | en_US |
| dc.subject | Rett syndrome | |
| dc.subject | MeCP2 | |
| dc.subject | MeCP2-T158M mutation | |
| dc.subject | Simvastatin | |
| dc.title | Investigating the therapeutic effects of simvastatin on a mouse model of Rett syndrome | |
| dc.type | master thesis | en_US |
| local.subject.manitoba | no |