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Elevating expression of MeCP2 T158M rescues DNA binding and Rett syndrome-like phenotypes
The Journal of Clinical Investigation
|April 11, 2017
Summary
Increasing methyl-CpG-binding protein 2 (MeCP2) levels, even with the T158M mutation, can reverse Rett syndrome (RTT) like symptoms in mice. This suggests targeting MeCP2 protein expression or stability may be a viable therapeutic strategy for RTT.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene.
- Restoring MeCP2 expression in mouse models reverses RTT-like phenotypes, indicating potential therapeutic avenues.
Purpose of the Study:
- To develop and characterize a knockin mouse model for the common MeCP2 T158M mutation.
- To investigate the impact of the T158M mutation on MeCP2 function and RTT-like phenotypes.
- To explore therapeutic strategies targeting MeCP2 T158M expression or stability.
Main Methods:
- Development of MeCP2 T158M knockin mice.
- Assessment of MeCP2 protein levels, DNA binding, and degradation pathways.
- Evaluation of RTT-like phenotypes including motor function and respiration.
Main Results:
- The MeCP2 T158M mutation impairs DNA binding and leads to age-dependent protein destabilization and RTT-like phenotypes.
- Elevating MeCP2 T158M expression ameliorated motor and respiratory deficits in mice.
- The ubiquitin/proteasome pathway degrades MeCP2 T158M, and its inhibition increases MeCP2 T158M levels.
Conclusions:
- Increased MeCP2 T158M protein expression is sufficient to mitigate RTT-like phenotypes.
- Targeting MeCP2 T158M expression or stability represents a promising therapeutic approach for Rett syndrome.
