• Gene expression
• Molecular neurobiology of cholinergic proteins
• Synapse formation
• Synaptic protein targeting
• Synaptic protein turnover
• Cytoskeletal assembly of synaptic proteins
• Transcriptional control of acetylcholinesterase
• Molecular determinants of acetylcholine receptor turnover;
• Promoter elements regulating synaptic acetylcholinesterase:
• Targeting and expression of neuronal acetylcholine receptors in the hippocampus.
My research focuses on how synaptic proteins are targeted to their subcellular and extracellular sites and what intracellular components are important in the regulation of their expression. The goals of the research are (1) to determine how innervation controls the synthesis and expression of acetylcholine receptors (AChR) and acetylcholinesterase (AChE), at the cholinergic synapse, (2) to identify which steps in gene expression are important in controlling AChE mRNA during synaptogenesis in muscle and in the CNS, (3) to examine the molecular basis for the metabolic stability of the nicotinic acetylcholine receptor at the neuromuscular junction, and (4) to understand how innervation controls the synthesis and targeting of AChRs in the hippocampus of the brain. As a first step in understanding the mechanisms regulating the expression of AChE we have chosen to study the genetic basis of the protein. This includes determining the structural nature of the transcripts and gene for AChE and identifying the controlling elements of the promoter necessary for muscle specific and nerve specific expression. We are asking how innervation influences the transcriptional and post-transcriptional control of AChE expression and localization and how the nerve acts to regulate the local activity of synaptic proteins through its influence on synapse associated nuclei. Studies of denervated and innervated muscle designed to determine how nervous input controls AChE expression in vivo permit a quantitative assesment of transcript levels and molecular forms of the enzyme. The molecular determinants controlling AChR targeting and accumulation at synaptic contacts in the hippocampus are studied using long term culture of organotypic hippocampal and septal/hippocampal slices of normal and AChR null mutant mice. These studies will provide a basic understanding of the means that synaptic proteins generate the concentration and the specific targeting found at the neuromuscular junction and in the CNS. They provide critical insights into the cholinergic control of neurotransmission associated with neurodegenerative diseases of cognition, such as Alzheimer’s dementia, Parkinsons disease, and schizophrenia.
• Tsim, K.W.K., I. Greenberg, M. Rimer, W.R. Randall, and M.M. Salpeter. Transcripts Encoding AChR and AChE in cultured chick muscle cells have different nuclear cytoplasmic domains. J. Cell Biol. 118, 1201-1212 (1992).
• Randall, W.R. Cellular expression of a cloned hydrophilic murine acetylcholinesterase: evidence of palmitoylated membrane-bound forms. J. Biol. Chem., 269, 12367-12374 (1994).
• Liu, Y., W.R Randall, and M.F. Schneider. Activity-dependent and –independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle. J. Cell Biol.168, 887-97 (2005).
• Cohen, T.V., and W.R. Randall. The AChE intron contains elements that regulate the response to chronic low-Frequency electrical stimulation. J.Neurochem. 98, 723-734 (2006)
• Albuquerque, E.X., E. F.R. Pereira, W.P. Fawcett, Y. Aracava, M. Oliveira, W.R Randall, T.A Hamilton., R.K. Kan, J.A. Romano Jr., and M. Adler. An effective treatment for organophosphorus poisoning. Proc.Nat.Acad.Sci. 103, 13220-13225 (2006)
• Cohen, T.V., and W.R. Randall. NFATc Activates the AChE Promoter in Rat Muscle. J. Neurochem. 90, 1059-1067 (2004)