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Identification of NUB1 as a Suppressor of Mutant Huntingtin Toxicity via Enhanced Protein Clearance

Lu, Boxun and Al-Ramahi, Ismael and Antonio, Valencia and Berenshteyn, Frada and Yang, Haidi and Gallego-Flores, Tatiana and Ichcho, Salah and Lacoste, Arnaud and Marian, Difiglia and Hild, Marc and Botas, Juan and Palacino, James and Wang, Qiong (2013) Identification of NUB1 as a Suppressor of Mutant Huntingtin Toxicity via Enhanced Protein Clearance. Nature Neuroscience. ISSN 1097-6256

Abstract

Huntington’s disease is caused by expanded CAG in HTT, conferring toxic gain of function to mutant HTT (mHTT) protein. Reducing mHTT levels is postulated as a strategy for therapeutic intervention. We conducted genome-wide RNAi screens for genes modifying mHTT levels and identified 13 hits. Ten were tested in vivo in a Drosophila Huntington’s disease model and 6 exhibited activity consistent with in vitro screening. Among these, NUB1 overexpression lowered mHTT in neuronal models, and rescued mHTT-induced death. NUB1 reduces mHTT level by enhancing poly-ubiquitination 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 modulate NUB1 for treatment, interferon beta (IFNβ) lowered mHTT and rescued neuronal toxicity via 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.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/5866

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