Elucidating the mechanisms by which synapses are altered for long-term memory storage is crucial for understanding both normal and abnormal functions of the nervous system. Investigations over the years have established that new gene transcription and translation of the newly transcribed genes is required for maintenance of long-term synaptic plasticity and consolidation of long-term memory. Research during the last two decades has revealed that proteolysis by the ubiquitin-proteasome pathway (UPP) has an essential role in synaptic plasticity and memory. Much of the work on the UPP has been focused on its traditional function, namely, degradation of substrate proteins. It is now becoming clear that the proteasome has other roles in the cell such as regulation of transcription. Studies carried out on non-neuronal cell types have shown that the proteasome binds to promoters of actively transcribed genes and assists in transcription. A part of the proteasome called the 19S regulatory complex contains several ATPases among which Rpt1 has been shown to play a critical role in transcription. We will investigate the role of the proteasome in transcription by focusing on Rpt1. We will use hippocampal late phase long-term potentiation (L-LTP) as a model system for our studies. Our preliminary data show that Rpt1 translocates to the nucleus in hippocampal slices in response to L-LTP- inducing stimuli. Also, our results show that Rpt1 binds to specific promoters of the brain-derived neurotrophic factor (BDNF) gene.
Our first aim i s to use a high-throughput sequencing method in combination with chromatin immunoprecipitation with Rpt1 antibodies to identify the transcriptional targets of Rpt1.
Our second aim i s to test the hypothesis that the function of nuclear Rpt1 is critical for transcription and L-LTP maintenance. This project will lay the groundwork for elucidating the unconventional roles of the proteasome in transcription required for long-term synaptic plasticity which will have significant implications for understanding normal long-term memory as well as loss of memory seen in many diseases and disorders of the brain. Furthermore, by providing hands-on research experience to undergraduate students, this project will significantly enhance the training of future biomedical scientists.
Memories form when connections between nerve cells called synapses change. Recent discoveries show that part of the nerve cells called the proteasome functions to control the function of genes. This project will study how the gene-regulating function of the proteasome contributes to change in synapses. Proteasome is important for normal function in the brain. Proteasome function is compromised in many diseases and disorders of the brain. This research could help explain how memory forms in the normal brain and how memory loss occurs in brain diseases.
|Hegde, Ashok N; van Leeuwen, Fred W (2017) Editorial: Ubiquitin and the Brain: Roles of Proteolysis in the Normal and Abnormal Nervous System. Front Mol Neurosci 10:220|