Recent Discoveries in Neurodegeneration by Fudan Researchers
Huntington's disease is a typical neurodegenerative disorder caused by an expanded polyglutamine-encoding repeat in the gene huntingtin (HTT) that leads to the accumulation of the mutant HTT protein (mHTT). With the aim of devising therapeutic strategies to reduce the levels of mHTT, principle investigators of Fudan University and Novartis Inc. carried out a genome-wide screen to identify modifiers of mHTT abundance. In Nature Neuroscience, they describe how negative regulator of ubiquitin-like protein 1 (NUB1) enhances the proteasomal degradation of mHTT and that interferon-β can be used to induce NUB1 expression and thus ameliorate the toxic effects of mHTT.
A genome-wide screen identified over 500 genes as modifiers of mHTT degradation. Of those, 363 had human homologues, so the authors evaluated their effects in two immortalized fibroblast lines from patients with Huntington's disease. They identified 13 genes that consistently and selectively modulated mHTT levels in these cells.
The authors subsequently validated these findings in a D. melanogaster model of Huntington's disease. They examined the levels of a mHTT fragment (NT-HTT128Q) encoded by an inducible transgene in the nervous system of fly strains carrying overexpression or loss-of-function alleles of the genes identified in the screen. This revealed that loss of function of the D. melanogaster NUB1 homologue led to increased levels of NT-HTT128Q and exacerbated NT-HTT128Q-induced motor impairments, whereas overexpression of human NUB1 had the opposite effects.
Further analyses of the effects of NUB1 in neuronal models, including neurons derived from induced pluripotent stem cells from patients with Huntingdon's disease, confirmed that NUB1 reduces the levels of mHTT and the formation of mHTT aggregates. This effect involved an increase in mHTT ubiquitination — a post-translational modification that targets mHTT for proteasomal degradation — and required CUL3 ubiquitin E3 ligase. Interestingly, treating fibroblasts derived from patients with Huntington's disease or primary mouse neurons expressing mHTT with interferon-β, which is known to induce NUB1 expression and is approved for clinical use, increased the levels of NUB1 and enhanced mHTT clearance, providing the first proof-of-concept for potential NUB1-targeting therapeutics.
The study has been recently published Nature Neuroscience as a research article1. Fudan investigator Dr. Boxun Lu has been the first and corresponding author, and Novartis investigator James Palacino has been the last and corresponding author. The article has been commented in Nature Neuroscience and received A+ recommendation in Nature Reviews Neuroscience.
Lu, B. et al. Identification of NUB1 as a suppressor of mutant Huntingtin toxicity via enhanced protein clearance. Nature Neurosci. 2013 May;16(5):562-70. doi: 10.1038/nn.3367