Human Molecular Genetics Advance Access originally published online on October 19, 2005
Human Molecular Genetics 2005 14(23):3643-3659; doi:10.1093/hmg/ddi392
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
RNA-binding protein is involved in aggregation of light neurofilament protein and is implicated in the pathogenesis of motor neuron degeneration
Division of Neuropathology, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA
* To whom correspondence should be addressed at: 609C Stellar-Chance Laboratories, Division of Neuropathology, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 422 Curie Boulevard, Philadelphia, PA 19104, USA. Tel: +1 2156627372; Fax: +1 2155732059; Email: wws435jp{at}mail.med.upenn.edu
Received August 18, 2005; Accepted October 13, 2005
Abnormal protein aggregation is emerging as a common theme in the pathogenesis of neurodegenerative disease. Our previous studies have shown that overexpression of untranslated light neurofilament (NF-L) RNA causes motor neuron degeneration in transgenic mice, leads to accumulation of ubiquitinated aggregates in degenerating cultured motor neurons and triggers aggregation of NF-L protein and co-aggregation of mutant SOD1 protein in neuronal cells. Here, we report that p190RhoGEF, an RNA-binding protein that binds to a destabilizing element in NF-L mRNA, is involved in aggregation of NF-L protein and is implicated in the pathogenesis of motor neuron degeneration. We show that p190RhoGEF co-aggregates with unassembled NF-L protein and that co-aggregation is associated with down-regulation of parent NF-L mRNA in neuronal cells. Co-expression of NF-M increases NF assembly and reduces RNA-triggered aggregation as well as loss of solubility of NF-L protein. siRNA-induced down-regulation of p190RhoGEF not only reduces aggregation and promotes assembly of NF-L and NF-M, but also causes reversal of aggregation and recovery of NF assembly in transfected cells. Examination of transgenic models of motor neuron disease shows that prominent aggregates of p190RhoGEF and NF-L and down-regulation of NF-L expression occur in degenerating motor neurons of mice expressing untranslated NF-L RNA or a G93A mutant SOD1 transgene. Moreover, aggregates of p190RhoGEF and NF-L appear as early pathological changes in presymptomatic G93A mutant SOD1 transgenic mice. Together, the findings indicate that p190RhoGEF is involved in aggregation of NF-L protein and support a working hypothesis that aggregation of p190RhoGEF and NF-L is an upstream event triggering neurotoxicity in motor neuron disease.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Lim, S.-T. Lim, A. Tomar, M. Gardel, J. A. Bernard-Trifilo, X. L. Chen, S. A. Uryu, R. Canete-Soler, J. Zhai, H. Lin, et al. PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility J. Cell Biol., January 10, 2008; 180(1): 187 - 203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhai, H. Lin, J.-P. Julien, and W. W. Schlaepfer Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot Marie Tooth disease-linked mutations in NFL and HSPB1 Hum. Mol. Genet., December 15, 2007; 16(24): 3103 - 3116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Mehler and J. S. Mattick Noncoding RNAs and RNA Editing in Brain Development, Functional Diversification, and Neurological Disease Physiol Rev, July 1, 2007; 87(3): 799 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. Schlaepfer, H. Lin, and J. Zhai Aggregation of Light Neurofilament Protein has Direct Neurotoxic Effect on Motor Neurons FASEB J, April 1, 2007; 21(5): A25 - A25.
|
|
|
|
|
|
R. J. Osborne and C. A. Thornton RNA-dominant diseases Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R162 - R169. [Abstract] [Full Text] [PDF]
|
|