George Tofaris
University of Oxford
United Kingdom
Development of small molecule Usp8 inhibitors as therapeutics in Lewy body dementia
Alzheimer's Research UK
67,780
01/10/2015
3
Lewy body disease is the second commonest cause of neurodegeneration. Lewy bodies are protein clumps inside brain cells, made of a small protein called ?-synuclein. Their build-up is critically dependent on the amount of ?-synuclein in the brain. Healthy cells remove damaged proteins, principally by attaching on them a tag, which acts as a signal for destruction. This tag (ubiquitin-chain) is regulated by a specialised cleanup crew inside cells. This includes factors that assemble the ubiquitin-chain, shuttle the chain inside cells and eventually disassemble it for recycling. If we understood this crew that clears ?-synuclein and turn it on or off using small molecules, then we could specifically reduce the accumulation of ?-synuclein and slowdown or stop the disease. Our lab has shown that one such factor, Usp8 is overactive around Lewy bodies trimming off ubiquitin from ?-synuclein, slowing down its breakdown. When Usp8 was blocked genetically it protected against toxicity from the abnormal accumulation of ?-synuclein. We now aim to test whether small molecules that block Usp8 have a beneficial effect without side-effects in brain cells that were derived from skin cells. If successful this study could open the way to novel therapies in this group of diseases.