Fellowship Award: Targeting the mGluR5-FMRP signaling pathway for the treatment of TSC
Grant holder and Fellow: Dr Sophie Thomson
University of Edinburgh
Tuberous sclerosis complex (TSC) is a developmental disorder caused by mutation in either the TSC1 or TSC2 genes resulting in symptoms such as tumour formation, seizures, and autism-like behaviour. The protein products of the TSC1 and TSC2 genes come together to form the TSC1/2 complex, which inhibits the mTOR pathway – a potent activator of mRNA translation. In TSC mouse models, mRNA translation is disrupted, leading to several pathological changes in synaptic function and learning. In this study, we will investigate the hypothesis that correcting protein synthesis defects can ameliorate pathological phenotypes in Tsc2+/- mice.
Studies in mice have shown that protein synthesis defects of the Tsc2+/- mouse can be corrected by two different strategies: 1) treatment with CDPPB, which is a metabotropic glutamate receptor 5 (mGluR5) positive allosteric modulator (PAM), and 2) down-regulation of the Fmr1 gene by crossing the Tsc2+/- mouse with an Fmr1-/y mouse.
The first aim of this study is to fully characterise the efficacy of CDPPB treatment and Fmr1 knockdown in the Tsc2+/- mouse on an anatomical, electrophysiological, and behavioural level. The second aim is to use translating ribosome affinity purification (TRAP) technology combined with RNA-seq to identify target mRNAs that are aberrantly expressed in the Tsc2+/- mouse, and how CDPPB treatment or Fmr1 knock down alters these mRNA transcripts. Together, these investigations will identify new therapeutic targets for the neurological symptoms of TSC.