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

Huntington's Disease (HD) is a devastating dementia disease. The alteration in a gene called huntingtin (htt) leads to changed Htt protein and its toxic aggregates, which in turn cause brain cell death and HD. Strong evidence has shown that cellular "self-eating "process, termed autophagy, counteracts dementia diseases such as HD because autophagy clears up protein aggregates in cells, thereby removing their toxicity to cells. Defects in autophagy give rise to various dementia diseases.

Bim is a critical protein that causes cell death in various tissues including those in brains. Recently we found that Bim also suppresses autophagy in addition to its cell death induction. Therefore, Bim are involved in autophagy inhibition and cell death induction, both of which are relevant to HD. Previously, Bim was shown to be increased in HD models, and we observed that reduction of Bim decreased toxic Htt protein aggregates and cell death in HD cells. These suggest that Bim may be an important driver for HD progression. Importantly, we identified a portion of Bim (Bim-P) capable of enhancing autophagy and reducing toxic Htt protein aggregates in HD cells. Based on the preliminary data, we will further establish the process that causes the increase of Bim protein in HD, examine if Bim contributes to HD progression and test the efficacy of Bim-P in treating HD using HD mouse models.

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.

Subjects related to autophagy and cell death are rapidly developing. The relevant research breakthrough has been published in high-impact journals and made headlines in mass media. Whilst significant progress has been made, many more mysteries need to solve so that diseases can be better treated through knowledge. This project will generate such important scientific data, advancing our knowledge in the pathogenesis and therapy of Huntington's Disease (HD) as well as other neurodegenerative diseases. Importantly, this research area is underrepresented in UK at the time being, and our study will significantly contribute to UK's leading position in the field.

Neurodegenerative diseases, such as Huntington's Disease, Alzheimer's Disease and Parkinson's Disease, have tremendous influence on our lives in 21st century. Autophagy and apoptosis are closely linked with these diseases. This study will benefit patients by investigating the potential role of Bim as a driving factor to HD progression and testing the efficacy of a therapeutic agent in treating HD.

The proposed project will be a platform to train a post-doctoral scientist. He/she will have opportunities to gain or improve a wide range of knowledge and expertise in biochemistry, molecular and cellular biology and genetics. The training will be essential for professional scientists to work in either academia or industry. In addition, this project will be in connection with undergraduate and graduate students in Plymouth University Peninsula Schools of Medicine and Dentistry (PUPSMD) so that they can get involved in basic lab training, which will be important for them to explore their interests in scientific research in the future.

This study will generate world-class basic and drug-discovery study in HD and will significantly contribute to strengthening the reputation of PUPSMD. This project has potential to be translated into bedside medicine, and we will closely interact with a number of existing groups in PUPSMD who are working in translational medicine, and actively exchange ideas in the relevant areas, such as drug development and clinical trial.