As illustrated in our Logo, our lab isinterested in identifying novel therapeutic targets and drugs for neurodegenerativedisorders, such Huntington's disease (HD), a monogenetic neurodegenerativedisorder.
Our lab has been focusing on the mutant HTT protein (mHTT), which is the major cause of the disease. Based on reliable evidence in the field and in our lab, lowering mHTT level is the most promising approach for HD treatment as illustrated below.
We thus established a series of unbiasedhigh-throughput assays to measure the steady-state level as well as thedegradation rate of the By this approach, we identified a number of promisingtargets and candidate drugs for HD treatment by lowering mHTT levels, demonstrated in a number of disease models including mouse HD neurons, HD patient iPS-derived neurons, HD flies, and HD knockin mouse models.
MAPK11 and HIPK3:
Measurement of mHTT degradation and screeningfor genetic modifiers of mHTT degradation also revealed novel insights into HDdisease mechanisms.
Interestingly, we revealed that mHTT hasconformational polymorphism, leading to highly toxic species with slowerdegradation:
In addition, mHTT activates downstream kinaseswhich stabilizes itself, forming a positive feedback loop that may contributeto disease progression:
Recently, we established compoundchip-based assays to screen for compounds that directly interact with mHTT, andrevealed a number of compounds binding with mHTT specially but not wtHTT. Interestingly,many of these compounds rescued HD-relevant phenotypes, likely via targetingmHTT and altering its conformation directly. We are currently working onresolving their mechanism of action, which may not only provide promising HDdrugs, but also HD mechanisms by these chemical biology tools.