RNA-binding protein is involved in aggregation of light neurofilament protein and is implicated in the pathogenesis of motor neuron degeneration.

Abstract

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.

• Authors: Hong Lin, Jinbin Zhai, William W Schlaepfer
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 14 Issue 23 Pg. 3643-59 (Dec 01 2005) ISSN: 0964-6906 [Print] England
• PMID: 16236762 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Arhgap35 protein, mouse
• Carrier Proteins
• DNA-Binding Proteins
• GTPase-Activating Proteins
• Neurofilament Proteins
• RNA, Messenger
• RNA-Binding Proteins
• Repressor Proteins
• neurofilament protein L
• neurofilament protein M

Topics

• Animals
• Carrier Proteins (analysis, genetics, metabolism)
• DNA-Binding Proteins
• GTPase-Activating Proteins
• Mice
• Mice, Transgenic
• Motor Neuron Disease (genetics, metabolism, pathology)
• Motor Neurons (chemistry, metabolism)
• Nerve Degeneration (genetics, metabolism)
• Neurofilament Proteins (analysis, genetics, metabolism)
• RNA Interference
• RNA Stability
• RNA, Messenger (metabolism)
• RNA-Binding Proteins (analysis, genetics, metabolism)
• Repressor Proteins
• Solubility