A Role for Huntington Disease Protein in Dendritic RNA Granules

• Published in: The Journal of biological chemistry Vol. 285; no. 17; pp. 13142 - 13153
• Main Authors: Savas, Jeffrey N., Ma, Bin, Deinhardt, Katrin, Culver, Brady P., Restituito, Sophie, Wu, Ligang, Belasco, Joel G., Chao, Moses V., Tanese, Naoko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.04.2010; American Society for Biochemistry and Molecular Biology
• Subjects: 3' Untranslated Regions - physiology; Animals; Argonaute Proteins; Biological Transport - physiology; Cytoplasmic Granules - genetics; Cytoplasmic Granules - metabolism; Dendrites - metabolism; Eukaryotic Initiation Factor-2 - genetics; Eukaryotic Initiation Factor-2 - metabolism; Gene Knockdown Techniques; Gene Silencing; Huntingtin Protein; Huntington Disease; Membrane Proteins - genetics; Membrane Proteins - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neurodegeneration; Neuronal RNA Granules; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; P-body; Post-transcriptional Gene Silencing; Protein Biosynthesis - physiology; Rats; Rats, Wistar; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; RNA; RNA Silencing; RNA Transport; Huntington Disease; P-body; RNA Transport; Neurodegeneration; Gene Silencing; RNA Silencing; Neuronal RNA Granules; Post-transcriptional Gene Silencing
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.114561

Regulated transport and local translation of mRNA in neurons are critical for modulating synaptic strength, maintaining proper neural circuitry, and establishing long term memory. Neuronal RNA granules are ribonucleoprotein particles that serve to transport mRNA along microtubules and control local protein synthesis in response to synaptic activity. Studies suggest that neuronal RNA granules share similar structures and functions with somatic P-bodies. We recently reported that the Huntington disease protein huntingtin (Htt) associates with Argonaute (Ago) and localizes to cytoplasmic P-bodies, which serve as sites of mRNA storage, degradation, and small RNA-mediated gene silencing. Here we report that wild-type Htt associates with Ago2 and components of neuronal granules and co-traffics with mRNA in dendrites. Htt was found to co-localize with RNA containing the 3′-untranslated region sequence of known dendritically targeted mRNAs. Knockdown of Htt in neurons caused altered localization of mRNA. When tethered to a reporter construct, Htt down-regulated reporter gene expression in a manner dependent on Ago2, suggesting that Htt may function to repress translation of mRNAs during transport in neuronal granules.