Healthy cognitive function depends upon the correct regulation of specific targeted genes in response to incoming stimuli. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with well-established roles in neuronal survival, differentiation, and synaptic plasticity. BDNF can regulate gene expression at the levels of both transcription and translation. Several functions of BDNF, including dendrite outgrowth and long-term synaptic plasticity, are known to explicitly depend upon the ability of BDNF to regulate protein synthesis. BDNF modestly increases total neuronal protein synthesis by enhancing the activity of translation initiation and elongation factors to globally induce the protein synthesis machinery. However, BDNF demonstrates an extraordinary degree of transcript specificity and strongly upregulates the translation of a small percentage of targets, while leaving some targets unaffected and downregulating the translation of others. This striking transcript selectivity is critical to the control of neuronal protein composition by BDNF and its role as a trophic factor. We recently delineated a pathway by which BDNF controls specificity in protein synthesis through both positively and negatively regulating the biogenesis of mature miRNAs to determine whether specific gene transcripts are repressed or undergo enhanced translation. The focus of this proposal is to examine the molecular mechanisms by which BDNF controls miRNA biogenesis, the spatial and temporal aspects of this regulation, and the role of these novel pathway components in cognitive function. Results from our investigations wil reveal previously unknown mechanisms controlling the specificity of gene expression and offer potential new therapeutic targets for the treatment of brain disorders with particular relevance to processes, such as Autism, Fragile X syndrome, depression, and neurodegenerative disease, with known links to BDNF, dysregulated translation, or both.
Dysregulation of BDNF signaling pathways in animal models produces both neurodevelopment and cognitive defects, while human gene polymorphisms in BDNF have been associated with neurocognitive defects including memory deficits, autism, schizophrenia, and obsessive-compulsive disorders. Enhancing BDNF expression can mitigate cognitive defects associated with a variety of neurological disorders, including Alzheimer's disease, depression, brain trauma, and age-related dementia. Our proposal will reveal novel mechanisms, and potential new therapeutic targets, which operate downstream of BDNF to determine its effects on the neuronal proteome.
|Amen, Alexandra M; Ruiz-Garzon, Claudia R; Shi, Jay et al. (2017) A Rapid Induction Mechanism for Lin28a in Trophic Responses. Mol Cell 65:490-503.e7|
|Ruiz, Claudia R; Shi, Jay; Meffert, Mollie K (2014) Transcript specificity in BDNF-regulated protein synthesis. Neuropharmacology 76 Pt C:657-63|