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William
W. Schlaepfer, M.D.
Professor, Dept of Pathology and Laboratory Medicine
School of Medicine
609C Stellar Chance Labs/6100
(215) 662-7372 FAX - (215) 573-2069
email: wws435jp@mail.med.upenn.edu
Click here for selected publications since Dr. Schlaepfer's arrival at Penn
RESEARCH INTERESTS
Mechanisms whereby overexpression of a destabilizing element in NF-L RNA or cognate RNA-binding proteins lead to motor neuron degeneration RESEARCH TECHNIQUES
In vivo and in vitro interactions of NF-L RNA and cognate binding factors and their effects on motor neuron cultures, neuronal cell lines, stem cells cultures as well as on motor neurons of transgenic, knock-out and knock-in mice. In vitro studies include of RNA-protein (gel retardation, UV cross-linkage and Northwestern) and protein-protein (farwestern, 2-hybrid, GST pulldown and immunoprecipition assays) interactions of NF-L RNA elements, cognate RNA binding factors and NF-L protein.RESEARCH SUMMARY
Our studies are directed at the mechanisms whereby expression of untranslated NF-L RNA causes motor neuron degeneration. We have reproduced RNA-induced motor neuron degeneration in transgenic mice expressing a mutant NF-L transgene, in mice expressing untranslated NF-L mRNA in the 3'UTR of a GFP reporter transgene and by microinjecting or transfecting transgenes expressing untranslated NF-L mRNA into primary motor neurons in vitro . The latter studies show that RNA-induced motor neuron degeneration is dose-dependent and neuron-specific and leads to distal-to-proximal fragmentation of neurites with accumulation of ubiquitinated aggregates in degenerating motor neurons. The neurotoxic properties map to a 45 nt destabilizing element in the proximal 3'UTR of NF-L mRNA and are associated with alterations of p190RhoGEF, a cognate RNA-binding protein that binds to the destabilizing element and stabilizes NF-L mRNA. p190RhoGEF also interacts with NF-L protein, is able to distinguish assembled vs unassembled subunits and links the disposition of NF-L protein with stabilization of NF-L mRNA. Our working hypothesis is that interactions of p190RhoGEF with NF-L mRNA and NF-L protein act as a feedback mechanism to maintain NF-L expression in accordance with levels of NF-L assembly and with levels of NF metabolism in the neuron. We believe that perturbations of p190RhoGEF and associated alterations in the feedback pathway can disrupt neuronal homeostasis and lead to dysfunctional and neurodegenerative states. Studies are currently underway to examine the interactions of p190RhoGEF with NF-L mRNA and NF-L protein in models of motor neuron degeneration.
The Schlaepfer Lab
