TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor

• Published in: Journal of neurochemistry Vol. 105; no. 3; pp. 797 - 806
• Main Authors: Wang, I.-Fan, Wu, Lien-Szn, Chang, Hsiang-Yu, Shen, C.-K. James
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.05.2008; Blackwell Publishing Ltd; Blackwell
• Subjects: Actins - metabolism; Ageing, cell death; Animals; Biochemistry; Biological and medical sciences; Brain damage; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cell physiology; Cells, Cultured; Cellular biology; Cytoplasmic Granules - metabolism; Cytoplasmic Granules - ultrastructure; Dementia - metabolism; Dementia - physiopathology; Dendrites - metabolism; Dendrites - ultrastructure; depolarization; Disks Large Homolog 4 Protein; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fragile X Mental Retardation Protein - metabolism; Fundamental and applied biological sciences. Psychology; Hippocampus - metabolism; Hippocampus - ultrastructure; Intracellular Signaling Peptides and Proteins - metabolism; Membrane Proteins - metabolism; Molecular and cellular biology; Neurology; neuronal dendrites; Neuronal Plasticity - physiology; Neurons - metabolism; Neurons - ultrastructure; processing body; Protein Biosynthesis - genetics; Proteins; Rats; Responses to growth factors, tumor promotors, other factors; RNA granules; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-binding proteins; RNA-Binding Proteins - metabolism; TDP-43; Biological transport; Central nervous system; RNA-binding proteins; RNA granules; In vitro; neuronal dendrites; Encephalon; Depolarization; Binding protein; Neuron; Actin; TDP-43; Plasticity; processing body; Development; Degeneration; Transcription factor; Hippocampus
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.05190.x

TDP-43, recently identified as a signature protein of the pathogenic inclusions in the brains cells of frontotemporal lobar degeneration patients, is a 43 kDa RNA-binding protein. It has been known mainly as a nuclear factor capable of repressing transcription and promoting exon exclusion. TDP-43 also forms distinct nuclear substructures linking different types of nuclear bodies. In this study, we provide the first evidence supporting TDP-43 as a neuronal activity-responsive factor in the dendrites of hippocampal neurons. In particular, TDP-43 resides in the somatodendrites mainly in the form of RNA granules colocalized with the post-synaptic protein PSD-95. These granules also contain RNAs including at least the β-actin mRNA and CaMKIIα mRNA. Furthermore, TDP-43 is localized in the dendritic processing (P) body and it behaves as a translational repressor in an in vitro assay. Related to this, repetitive stimuli by KCl greatly enhance the colocalization of TDP-43 granules with FMRP and Staufen 1, two RNA-binding proteins known to regulate mRNA transport and local translation in neurons. These data together suggest that TDP-43 is a neuronal activity-responsive factor functioning in the regulation of neuronal plasticity, the impairment of which would lead to the development of certain forms of neurodegenerative diseases including frontotemporal lobar degeneration.