Principal Investigators

    Dr S Luo


    University of Plymouth

    Contact information of lead PI


    United Kingdom

    Title of project or programme

    Tackling autophagy and apoptosis for the potential therapy of Huntington's Disease

    Source of funding information


    Total sum awarded (Euro)

    € 569,457

    Start date of award


    Total duration of award in years


    The project/programme is most relevant to:

    Huntington's disease


    Research Abstract

    Huntingtin’s Disease (HD) is a progressive neurodegenerative disorder, caused by mutant huntingtin gene (htt) with expanded CAG repeats, which are translated into expanded polyglutamine (polyQ) stretch. The expanded polyQ forms toxic aggregates that induce neuronal death. It has been well characterised that mutant Htt (mHtt) aggregates can be degraded by autophagy, a lysosome-dependent bulk degradation system, and autophagy upregulation ameliorates HD and other neurodegenerative diseases. Autophagy consists of autophagosome synthesis (cargo delivery) and autophagosome-lysosome fusion (cargo degradation). The initiation of autophagosome synthesis is tightly regulated by a set of autophagy genes, such as Atg1, Beclin 1 and class III PI-3 kinase Vps34. The Beclin 1-Vps34 localisation at ER is critical for the formation of autophagosomes. We found that pro-apoptotic protein Bim restricts Beclin 1-Vps34 complex to microtubules away from its functional site ER, thereby suppressing autophagy. Bim is therefore a dual regulator that promotes apoptosis but inhibits autophagy. Our preliminary data show that the protein and mRNA levels of Bim were significantly enhanced in human HD post-mortem striatum, confirming previous data that Bim levels are increased in HD mouse and cell models. Collectively, these suggest that Bim may a driving factor to progression of HD pathology. We observed that depletion of Bim with RNA interference significantly reduced mutant Htt aggregation and toxicity in cells. Importantly, a peptide derived from Bim (Bim-P) promotes autophagy by antagonising Bim’s autophagy inhibition, and reduces mutant Htt aggregation and toxicity in HD in vitro. Based on the preliminary data, we will establish the mechanism by which Bim is upregulated in HD, examine the effect of Bim in HD progression in vivo using HD mouse models and test the efficacy of the Bim-P in treating the HD mouse models.

    Lay Summary

    Further information available at:

Types: Investments > €500k
Member States: United Kingdom
Diseases: Huntington's disease
Years: 2016
Database Categories: N/A
Database Tags: N/A

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