We focus on the mechanism of neurodegenerative disease (HD, PD and Cerebellar ataxias) and develop autophagy intervention strategies for diseases. We give two examples that made important contributions to the field as follows: (1) Excessive accumulation of lipid droplets (LDs) is one of the characteristics of neurodegeneration, lacking of tools to selectively reduce lipid droplets. We designed and developed LD.ATTEC technology for selectively targeting LDs degradation and rescuing LDs accumulation-related disease mouse phenotypes. In addition, the LD.ATTECs was highlighted in a commentary paper by Professor Ed Tate at Imperial College London, a Fellow of both the Royal Society of Chemistry and the Royal Society of Biology, “a rising star” and “open the stage for degradation of non-proteinaceous cellular components” etc. (2) Mutant HTT has different toxicity may be due to conformation. We revealed the relationship between conformation, degradation rate, and toxicity for mHTT, and elucidated the relationship between the source of toxicity mechanism and polyQ protein conformation polymorphism. This study may promote screening compounds that transit mHTT from toxic to nontoxic conformation, and indicated that treatment of monoclonal antibodies that recognize toxic conformations is of great therapeutic value.
A toxic mutant huntingtin species is resistant to selective autophagy (Yuhua Fu#, and Boxun Lu, Nature Chemical Biology, 2017)
Degradation of lipid droplets by chimeric autophagy-tethering compounds (Yuhua Fu, Yu ding and Boxun Lu, Cell Research, 2021)