Title: Compounds tethering autophagosmes and mutant HTT for clearance: a new strategy for selective removal
Funder: The Academy of Medical Sciences

Abstract: Reducing the disease-causing protein levels specifically by low-molecular-weight compounds is highly desired for disease research and treatment. General enhancement of autophagy may reduce harmful proteins, but in a relatively non-specific manner. We hypothesized that compounds interacting with both the autophagosome protein LC3 and the disease-causing proteins may target them for clearance by autophagy and reduce their levels specifically, without influencing other proteins that do not interact with these compounds. The applicant tested this hypothesis in the scenario of Huntingtonâ€™s disease (HD), which is an incurable neurodegenerative disorder mainly caused by cytotoxicity of the mutant HTT protein (mHTT). By compound-chip based high-throughput screening, we identified two compounds that interact with both LC3 and mHTT, but not wild-type HTT (wtHTT). Our preliminary data suggest that these compounds may reduce the mHTT level via autophagy in an allele-selective manner in HD neurons. In this project, we aim at resolving mechanistic details of mHTT lowering and phenotypic studies on potential therapeutic effects of these compounds. We will also expand this strategy to other proteins that may cause major neurodegenerative disorders. The host applicant has established expertise in autophagy, and the applicant has recognized track records in neurodegeneration research, especially mHTT and HD research. The two applicants have shared interest and have collaborated in recent years, and have published several collaborative research papers at top tier journals. In the proposed project, the two applicants aim at performing mechanistic and phenotypic studies of the allele-selective mHTT lowering by these mHTT-LC3 linker compounds, and the project is perfect match for the interest and expertise on both sides. Success of this collaboration will lay the basis for long-term partnership between them in demonstrating and developing this novel concept of regulating the target proteins by compounds that crosslink them with LC3 for their selective degradation via autophagy.

Lay abstract: Many diseases are caused by certain proteins inside the cells, and thus reducing these disease-causing proteins may provide promising therapeutic treatment for this diseases. Many of these proteins are cleared by autophagy, which is a key process degrading proteins inside the cells and its discovery won the 2016 Nobel Prize. Enhancement of autophagy may reduce the disease-causing proteins, but it also reduces all the other proteins that are degraded by autophagy, and this may cause problems. We have recently designed a strategy to discover compounds that serve as bridges to specifically target the disease protein to autophagy-mediated clearance, without influencing its normal form or other proteins. In our preliminary work, we have successfully utilized this strategy for the protein that causes Huntingtonâ€™s disease, which is an important devastating neurological disease. In this project, we will further investigate the effects of these compounds that we identified to see if they truly target the disease proteins to autophagy-mediated clearance and treat the disease. If successful, our results will not only provide candidate drugs for Huntingtonâ€™s disease, but also prove the concept of using compounds to specifically reduce target proteins, which are highly desired for treatment of other diseases as well.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL