Towards understanding and treatment of MeCP2-related disorders. (360G-Wellcome-107930_Z_15_Z)

£2,814,000

Mutations in the MECP2 gene are responsible for two autism spectrum disorders (ASDs): Rett Syndrome[1] (loss of function) and MECP2 Duplication Syndrome[2] (over-expression). Involvement in monogenic ASDs has prompted intensive study of MeCP2 protein, but its functional role remains uncertain. As either too little or too much MeCP2 protein leads to profound intellectual disability, understanding how this protein contributes to brain function is a priority. A prominent view is that MeCP2 is a multifunctional hub protein implicated in diverse pathways. A simpler alternative, suggested by the restricted distribution of Rett syndrome (RTT)-causing mutations, is that MeCP2 is primarily a transcriptional repressor that binds methylated DNA[3] and recruits a co-repressor complex[4]. This research programme is designed to distinguish these hypotheses through a series of experiments that challenge each. It will use the resulting basic knowledge to develop small molecules that may be used therapeutically. The following component questions will be addressed: 1. What are the determinants of MeCP2 binding to chromatin in vivo? Although the protein has been shown to bind methylated DNA, additional determinants have been proposed. 2. Is the ability to bind both DNA and NCoR/SMRT sufficient for MeCP2 function? Our previous work suggests that these two discrete interaction domains are of over-riding functional importance for MeCP2 function. We will create mutations in mice that test this hypothesis. 3. How and why is gene expression affected by varying levels of MeCP2? The reported effects of MeCP2-deficiency on brain gene expression are inconsistent, rangingfrom no clear effects, to mostly activation or mostly repression[5]. We will use homogeneouspopulations of cultured human neurons to resolve this question. 4. Can we identify therapeutic options for treatment of Rett syndrome and MECP2 Duplication Syndrome? Our earlier work established proof-of-principle that Rett syndrome is a reversible condition and therefore in principle curable[6]. So far, however, there are no effective treatments for any MeCP2-related condition. Based on our molecular insights into thebiochemical consequences of specific Rett mutations, we will collaboratively seek small molecules that stabilise or disrupt the structure/interactions of wildtype and mutant MeCP2.

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Grant Details

Amount Awarded 2814000
Applicant Surname Bird
Approval Committee Science Interview Panel
Award Date 2015-07-07T00:00:00+00:00
Financial Year 2014/15
Grant Programme: Title Investigator Award in Science
Internal ID 107930/Z/15/Z
Lead Applicant Prof Adrian Bird
Partnership Value 2814000
Planned Dates: End Date 2022-06-30T00:00:00+00:00
Planned Dates: Start Date 2016-01-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Scotland