One of the principal neuropathological features of Parkinson’s disease and dementia is the formation inside neurons of Lewy bodies. These ‘bodies’ are clumps of a sticky protein called alpha-synuclein that build up in nerve cells in the brain, causing damage and eventually death to these cells. Typically, they affect the brain cells that control movement.
One of the challenges in this area of research is the lack of models that faithfully recapitulate the pathological process that leads to Parkinson’s disease. To bypass this limitation, Dr George Tofaris and his team have used a diverse set of investigations, starting from observations in human pathological specimens which they then deciphered using simpler models such as neuronal cells, flies and biochemical studies with purified proteins.
Pharmacological inhibition of Usp8 using small molecules could pave the way to novel therapeutics. A major challenge ahead is to develop and assess these compounds in more complex systems such as patient-derived neuronal cells or mouse models.
- George Tofaris
We tend to get rid of alpha-synuclein protein quite slowly, using a sophisticated ‘clean-up crew’ of enzymes. By systematically assessing brains of people who have died as a result of DLB and PD, research at NDCN has shown that one of these enzymes is abnormally increased in the cells that contain the toxic protein clumps.
On the face of it, this may not seem to be a problem, but the system of waste-disposal enzymes is a complex one. They each play different roles and work together to regulate the level of alpha-synuclein. One set of the enzymes is responsible for directly attacking the protein whereas another-– that is abnormally increased in Parkinson’s cases – counteracts this action. This set of enzymes work in concert to either elongate or trim off a tag on alpha-synuclein, made of ubiquitin molecules. This tagging system is essentially “a kiss of death” for abnormal proteins because it targets them for destruction. Work in this study now suggests that the regulation of this “tagging” process goes awry in patients with Parkinson’s disease: one of the enzymes which removes the tag preventing degradation, called Usp8, is overactive and could at least partly explain why alpha-synuclein accumulates in neurons that eventually die. Importantly, reducing Usp8 appears protective in simple readouts of toxicity caused by alpha-synuclein accumulation in fly models.