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The Journal of Neuroscience, March 17, 2004, 24(11):2716-2726; doi:10.1523/JNEUROSCI.5689-03.2004

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Neurobiology of Disease
3' Untranslated Region in a Light Neurofilament (NF-L) mRNA Triggers Aggregation of NF-L and Mutant Superoxide Dismutase 1 Proteins in Neuronal Cells

Hong Lin, ^* Jinbin Zhai, ^* Rafaela Cañete-Soler, and William W. Schlaepfer

Division of Neuropathology, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104

The pathogenesis of neurodegenerative diseases is believed to involve abnormal aggregation of proteins, but the mechanisms initiating protein aggregation are unclear. Here we report a novel phenomenon that could be instrumental in triggering protein aggregation in neurodegenerative diseases. We show that the 3' untranslated region (3'UTR) of a light neurofilament (NF-L) transcript enhances the reactivity of its own translated product and leads to loss of solubility and aggregation of NF-L protein and to coaggregation of mutant superoxide dismutase 1 (SOD1) protein. Full-length mouse NF-L cDNAs, with and without NF-L 3'UTR, were fused to the C terminus of a green fluorescent protein (GFP) reporter gene, and the GFP-tagged NF-L proteins were examined in transfected Neuro2a cells. The GFP-tagged NF-L protein expressed from the transgene containing NF-L 3'UTR, but not from the transgene lacking NF-L 3'UTR, colocalizes with endogenous heavy neurofilament protein and, at high-level expression, leads to loss of solubility and aggregation of GFP-tagged NF-L protein. Aggregation of GFP-tagged NF-L protein triggers coaggregation and loss of solubility of coexpressed DsRed-tagged mutant (G93A) SOD1 protein but not wild-type SOD1 protein. Deletional mutagenesis maps the RNA sequence causing aggregation of GFP-tagged NF-L protein to the proximal 45 nucleotides of NF-L 3'UTR. This is the site of a major destabilizing element in NF-L RNA and binding site for RNA-binding proteins. Our findings support a working model whereby NF-L RNA, or cognate RNA-binding factors, enhances the reactivity of NF-L protein and provides a triggering mechanism leading to aggregation of NF-L and other proteins in neurodegenerative diseases.

Key words: neurofilament; RNA; mutant SOD1 protein; protein aggregation; ubiquitin; heat shock proteins; neuronal inclusions; neurodegeneration; polyglutamine expansion

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Received Oct 3, 2003; accepted February 2, 2004.

This article has been cited by other articles:

				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]

				H. Lin, J. Zhai, and W. W. Schlaepfer RNA-binding protein is involved in aggregation of light neurofilament protein and is implicated in the pathogenesis of motor neuron degeneration Hum. Mol. Genet., December 1, 2005; 14(23): 3643 - 3659. [Abstract] [Full Text] [PDF]

				J.-M. Gallo, P. Jin, C. A. Thornton, H. Lin, J. Robertson, I. D'Souza, and W. W. Schlaepfer The Role of RNA and RNA Processing in Neurodegeneration J. Neurosci., November 9, 2005; 25(45): 10372 - 10375. [Full Text] [PDF]

				J. Zhai, H. Lin, R. Canete-Soler, and W. W. Schlaepfer HoxB2 binds mutant SOD1 and is altered in transgenic model of ALS Hum. Mol. Genet., September 15, 2005; 14(18): 2629 - 2640. [Abstract] [Full Text] [PDF]

				R. Canete-Soler, K. S. Reddy, D. R. Tolan, and J. Zhai Aldolases A and C Are Ribonucleolytic Components of a Neuronal Complex That Regulates the Stability of the Light-Neurofilament mRNA J. Neurosci., April 27, 2005; 25(17): 4353 - 4364. [Abstract] [Full Text] [PDF]

				W.-W. Ge, W. Wen, W. Strong, C. Leystra-Lantz, and M. J. Strong Mutant Copper-Zinc Superoxide Dismutase Binds to and Destabilizes Human Low Molecular Weight Neurofilament mRNA J. Biol. Chem., January 7, 2005; 280(1): 118 - 124. [Abstract] [Full Text] [PDF]

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