Tuberous Sclerosis Complex (TSC) affects approximately 1 in 6,000 people and presents with multiple neurological symptoms including, mental disability, autism, and epilepsy. TSC is caused by autosomal dominant inactivating mutations in either the TSC1 or TSC2 genes. Normally, TSC1 and TSC2 proteins heterodimerize and form a protein complex that ultimately inhibits mammalian Target of Rapamycin (mTOR), a kinase that regulates activity-dependent dendritic protein translation in the nervous system. Disease associated mutations in TSC1 or TSC2 results in persistent activation of mTOR, which results in learning and memory deficits, aberrant synaptic plasticity, epilepsy and a host of other symptoms. Rapamycin based drugs (rapalogues) that inhibit mTOR show promise in treating TSC. However, long-term inhibition of mTOR is known to activate other growth factor pathways, the chronic effects of which are either unknown or are linked to cancer progression and malignancy. Thus, new classes of drugs are required to mitigate the neurological symptoms associated with TSC. Using novel bioinformatics approaches, we have found that the transcription factor RE-1 Silencing Transcription Factor (REST) displays heightened function in human patient TSC cortical samples: in a screen of 189 transcription factors, REST target genes are the most differentially expressed between human TSC cortical samples and non-TSC samples. Moreover, our preliminary data demonstrate that i) REST protein levels are elevated in the TSC2 mutant mouse hippocampus and ii) pharmacological inhibition of HDAC1/2 (obligate cofactors for REST) restores appropriate plasticity in a mouse model of TSC. In this proposal, we will test the hypothesis that loss of TSC1 or TSC2 leads to enhanced REST function (epigenetic disregulation), which results in the altered synaptic plasticity seen in TSC.
The Aims will be:
Aim 1. Test the hypothesis that elevated REST is necessary and sufficient for aberrant plasticity.
Aim 2. Test the hypothesis that antagonizing REST corepressors suppresses aberrant LTD and LTP in TSC. Should the hypothesis ?REST function is heightened to promote aberrant plasticity in TSC? be supported, an entirely new repetoire of drugs could potentially become available to treat the neurological symptoms associated with TSC.
Tuberous Sclerosis Complex is a condition that has a prevalence of 1 in 6000 people. It is caused by inactivating mutations in either the TSC1 or TSC2 gene and presents with various neurological symptoms including autism, epilepsy and cognitive impairment. Mouse models of the disease show alterations in synaptic plasticity in the hippocampus such as induction of LTP with stimuli that do not elicit LTP in WT animals. LTD is diminished in young TSC2 mutant mice and has altered signaling pathways in adults. Thus, much is known about the signal transduction pathways and translation that is altered by TSC1 or TSC2 mutations. However, nothing is known about the role of transcription in the plasticity alterations observed in TSC. This application will explore the role of altered transcription in TSC.
| Dingledine, Raymond; Coulter, Douglas A; Fritsch, Brita et al. (2017) Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models. Sci Data 4:170061 |
