A Role for Huntington Disease Protein in Dendritic RNA Granules

Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2010; 285(17):13142-53. DOI: 10.1074/jbc.M110.114561
Source: PubMed


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.

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Available from: Jeffrey N Savas, Jan 19, 2015
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    • "The widespread localization of Htt makes it diffi cult to determine its function; however, it has become clear that Htt operates at many cellular levels (Li and Li , 2004 ). Wild-type Htt has antiapoptotic properties (Rigamonti et al. , 2000, 2001 ), acts as a general facilitator of transcription (Futter et al. , 2009 ) and plays an important role in endocytosis (DiFiglia et al. , 1995 ; Velier et al. , 1998 ), intracellular vesicle traffi cking (Gauthier et al. , 2004 ; Caviston and Holzbaur , 2009 ), membrane recycling (Hilditch -Maguire et al., 2000 ) and, recently, in posttranscriptional transport/targeting of mRNA in association with neuronal RNA granules (Savas et al. , 2010 ). "
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    ABSTRACT: Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion of CAG repeats in the HD gene encoding for huntingtin (Htt), resulting in progressive death of striatal neurons, with clinical symptoms of chorea, dementia and dramatic weight loss. Metabolic and mitochondrial dysfunction caused by the expanded polyglutamine sequence have been described along with other mechanisms of neurodegeneration previously described in human tissues and animal models of HD. In this review, we focus on mitochondrial and metabolic disturbances affecting both the central nervous system and peripheral cells, including mitochondrial DNA damage, mitochondrial complexes defects, loss of calcium homeostasis and transcriptional deregulation. Glucose abnormalities have also been described in peripheral tissues of HD patients and in HD animal and cellular models. Moreover, there are no effective neuroprotective treatments available in HD. Thus, we briefly discuss the role of creatine and coenzyme Q10 that target mitochondrial dysfunction and impaired bioenergetics and have been previously used in HD clinical trials.
    Full-text · Article · Dec 2011 · Reviews in the neurosciences
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    • "A representative result demonstrating the trafficking dynamics of β-actin RNA is summarized in Supplementary Table S1 online. The average velocity of mRNA granules measured was 0.0294 ± 0.0215 μm/s, which is comparable to our previously recorded values for trafficking mRNAs visualized by SYTO RNASelect (average velocity: 0.04 μm/s)25. "
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    ABSTRACT: Transport of mRNAs to diverse neuronal locations via RNA granules serves an important function in regulating protein synthesis within restricted sub-cellular domains. We recently detected the Huntington's disease protein huntingtin (Htt) in dendritic RNA granules; however, the functional significance of this localization is not known. Here we report that Htt and the huntingtin-associated protein 1 (HAP1) are co-localized with the microtubule motor proteins, the KIF5A kinesin and dynein, during dendritic transport of β-actin mRNA. Live cell imaging demonstrated that β-actin mRNA is associated with Htt, HAP1, and dynein intermediate chain in cultured neurons. Reduction in the levels of Htt, HAP1, KIF5A, and dynein heavy chain by lentiviral-based shRNAs resulted in a reduction in the transport of β-actin mRNA. These findings support a role for Htt in participating in the mRNA transport machinery that also contains HAP1, KIF5A, and dynein.
    Full-text · Article · Nov 2011 · Scientific Reports
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    • "We previously reported that Htt co-localizes with Ago2 in processing (P)-bodies of somatic cells and neuronal granules [9,10] suggesting that Htt may play a role in RNA processing and/or gene silencing. To determine if Htt co-localizes with specific mRNAs in neuronal granules, which are structurally and functionally related to P-bodies [32], we utilized multicolor IFS and FISH techniques in concert with 3D co-localization to follow the expression of individual molecules in rat brain. "
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    ABSTRACT: Studies have implicated reduced levels of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Huntington's disease. Mutant huntingtin (Htt) protein was previously reported to decrease BDNF gene transcription and axonal transport of BDNF. We recently showed that wild-type Htt is associated with the Argonaute 2 microRNA-processing enzyme involved in gene silencing. In dendrites, Htt co-localizes with components of neuronal granules and mRNAs, indicating that it might play a role in post-transcriptional processing/transport of dendritic mRNAs. We conducted imaging experiments in cultured cortical neurons to demonstrate the co-localization of endogenous Htt and BDNF mRNA in fixed cells, and co-trafficking of BDNF 3'UTR mRNA with endogenous and fluorescently tagged Htt in live neurons. We used an enhanced technique that combines FISH and immunofluorescent staining to co-localize BDNF mRNA with Htt, Ago2, CPEB and dynein in thick vibratome sections of the rat cortex. In cultured neurons and sections of the rat cortex, we found BDNF mRNA associated with Htt and components of neuronal RNA granules, which are centers for regulating RNA transport and local translation. Htt may play a role in post-transcriptional transport/targeting of mRNA for BDNF, thus contributing to neurotrophic support and neuron survival.
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