This proposal will probe molecular mechanisms underlying motor neuron degeneration arising from abnormal NF gene expression. The proposed studies are based on recent discoveries that NF-induced motor neuron degeneration in transgenic mice is due to expression of untranslated neuropathic elements in the 3'UTR of NF-L mRNA. RNA-mediated neuronal degeneration is believed to be mediated by RNA-binding proteins that bind to and regulate the processing of NF-L mRNA and other neuronal transcripts. The presence of neuropathic RNA elements is believed to bind and alter the compositions of RNA-binding proteins in a manner that impairs their ability to maintain the viability of motor neurons. The proposed studies will utilize primary cultures of motor neurons as an in vitro model to identify and characterize the cis-acting elements and trans-acting factors mediating the neuropathic effects of NF-L mRNA. Neuropathic mutations will be introduced into the 3'UTR of endogenous NF-L genes by homologous recombination and the targeted mutations incorporated into the mouse genome by breeding chimeric mice. In this manner, untranslated neuropathic elements will be expressed in a NF-specific pattern in mice bearing a heterozygous or homozygous mutation. The mutant mice should provide a more reproducible phenotype for probing underlying alterations in RNA-mediated pathology in vivo, for examining the synergistic effects of RNA-mediated phenomena on mSOD-1-mediated motor neuron degeneration and for testing the modulating effects of trans-acting factors on RNA-mediated and mSOD-1 mediated motor neuron degeneration

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037552-07
Application #
7033909
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Refolo, Lorenzo
Project Start
1998-12-20
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
7
Fiscal Year
2006
Total Cost
$296,008
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhai, Jinbin; Lin, Hong; Canete-Soler, Rafaela et al. (2005) HoxB2 binds mutant SOD1 and is altered in transgenic model of ALS. Hum Mol Genet 14:2629-40
Lin, Hong; Zhai, Jinbin; Canete-Soler, Rafaela et al. (2004) 3' untranslated region in a light neurofilament (NF-L) mRNA triggers aggregation of NF-L and mutant superoxide dismutase 1 proteins in neuronal cells. J Neurosci 24:2716-26
Lin, Hong; Zhai, Jinbin; Nie, Zhenying et al. (2003) Neurofilament RNA causes neurodegeneration with accumulation of ubiquitinated aggregates in cultured motor neurons. J Neuropathol Exp Neurol 62:936-50