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Lu, B., Al-Ramahi, I., Valencia, A., Wang, Q., Berenshteyn, F., Yang, H., Gallego-Flores, T., Ichcho, S., Lacoste, A., Hild, M., Difiglia, M., Botas, J., Palacino, J. (2013). Identification of NUB1 as a suppressor of mutant Huntingtin toxicity via enhanced protein clearance.  Nat. Neurosci. 16(5): 562--570.
FlyBase ID
FBrf0221408
Publication Type
Research paper
Abstract

Huntington's disease is caused by expanded CAG repeats in HTT, conferring toxic gain of function on mutant HTT (mHTT) protein. Reducing mHTT amounts is postulated as a strategy for therapeutic intervention. We conducted genome-wide RNA interference screens for genes modifying mHTT abundance and identified 13 hits. We tested 10 in vivo in a Drosophila melanogaster Huntington's disease model, and 6 exhibited activity consistent with the in vitro screening results. Among these, negative regulator of ubiquitin-like protein 1 (NUB1) overexpression lowered mHTT in neuronal models and rescued mHTT-induced death. NUB1 reduces mHTT amounts by enhancing polyubiquitination and proteasomal degradation of mHTT protein. The process requires CUL3 and the ubiquitin-like protein NEDD8 necessary for CUL3 activation. As a potential approach to modulating NUB1 for treatment, interferon-β lowered mHTT and rescued neuronal toxicity through induction of NUB1. Thus, we have identified genes modifying endogenous mHTT using high-throughput screening and demonstrate NUB1 as an exemplar entry point for therapeutic intervention of Huntington's disease.

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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Nat. Neurosci.
    Title
    Nature Neuroscience
    Publication Year
    1998-
    ISBN/ISSN
    1097-6256
    Data From Reference
    Alleles (10)
    Genes (11)
    Human Disease Models (1)
    Natural transposons (1)
    Insertions (4)
    Experimental Tools (2)
    Transgenic Constructs (6)