TDP43 is a human low molecular weight neurofilament ( hNFL) mRNA-binding protein

The human TAR DNA-binding protein (TDP43) colocalizes with ubiquitinated inclusions in motor neurons in amyotrophic lateral sclerosis (ALS). TDP43 is both a DNA-binding protein with a nuclear export sequence that interacts with (TG) nT m elements in DNA and an RNA-binding protein that interacts with...

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Bibliographic Details
Published in:	Molecular and cellular neuroscience 2007-06, Vol.35 (2), p.320-327
Main Authors:	Strong, Michael J., Volkening, Kathryn, Hammond, Robert, Yang, Wencheng, Strong, Wendy, Leystra-Lantz, Cheryl, Shoesmith, Christen
Format:	Article
Language:	eng
Subjects:	3' Untranslated Regions - physiology Adult Aged Aged, 80 and over Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - pathology Base Sequence Brain - pathology Cell Line, Transformed DNA-Binding Proteins - metabolism Electrophoretic Mobility Shift Assay Female Humans Immunoprecipitation Male Middle Aged Molecular Weight Motor Neurons - metabolism mRNA stability Neurofilament Neurofilament Proteins - genetics Neurofilament Proteins - metabolism Protein Binding - physiology Protein Structure, Tertiary RNA, Messenger - genetics RNA, Messenger - metabolism Spinal Cord - pathology Transfection Translational regulation Ubiquitin - metabolism
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Summary:	The human TAR DNA-binding protein (TDP43) colocalizes with ubiquitinated inclusions in motor neurons in amyotrophic lateral sclerosis (ALS). TDP43 is both a DNA-binding protein with a nuclear export sequence that interacts with (TG) nT m elements in DNA and an RNA-binding protein that interacts with (UG) 6–12 motifs in single–stranded RNA. In control motor neurons, TDP43 was almost exclusively nuclear, whereas in ALS spinal motor neurons, TDP43 was predominantly localized to the cytosol and not the nucleus. TDP43 was observed as punctuate immunoreactivity and as dense skeins, with and without ubiquitinization. We observed that TDP43 stabilizes the human low molecular weight ( hNFL) mRNA through a direct interaction with the 3′UTR. TDP43 is a unique hNFL mRNA-binding protein that is altered in its somatotopic localization in ALS spinal motor neurons and potentially contributes to the formation of NF aggregates in ALS through alterations in NF stoichiometry.
ISSN:	1044-7431 1095-9327