USP13 Inhibition Clears Lewy Bodies in a Mouse Model of Parkinson's Disease
Many age-related conditions are associated with solid aggregates in tissues that are formed of altered, damaged, or misfolded proteins. Protein aggregates are thought to be an important contributing cause of these diseases. In most cases the proteins involved in aggregate formation can and do appear in lesser amounts in young tissues, but we can point to underlying problems that might explain why aggregates only appear in significant amounts in old tissues. Failure of clearance via fluid flow or the actions of immune cells for intracellular aggregates, or failure of clearance via autophagy within cells, for example. Near all processes in cellular metabolism falter with age, and increasing amounts of molecular waste is one of the many detrimental consequences.
Aging is in some ways a garbage catastrophe, and removal of aggregates is an important strategy for the treatment of aging as a medical condition. This has unfortunately proven to be a challenging task, particular for those aggregates that form primarily in the brain. The Alzheimer's research community required decades and a great deal of funding to get to the point of even preliminary success in the removal of amyloid-β via immunotherapies, for example. In the case of Parkinson's disease and α-synuclein aggregates, the situation is much the same: slow progress. Thus all novel possibilities for the removal of aggregates associated with neurodegenerative disease should be warmly welcomed.
A defining feature of Parkinson's disease is the clumps of alpha-synuclein protein that accumulate in the brain's motor control area, destroying dopamine-producing neurons. Natural processes can't clear these clusters, known as Lewy bodies, and no one has demonstrated how to stop the build up as well as breakdown of the clumps - until perhaps now. A team of neurologists has found through studies in mice and human brains that one reason Lewy bodies develop is that a molecule, USP13, has removed all the "tags" placed on alpha-synuclein that mark the protein for destruction. Toxic heaps of alpha-synuclein accumulate, and are never taken away. The findings show that inhibiting USP13 in mouse models of Parkinson's disease both eliminated Lewy bodies and stopped them from building up again.
The "tag" that USP13 removes is called ubiquitin, which labels alpha-synuclein for degradation. Parkin is one of a family of ubiquitin ligase enzymes. Ubiquitination is a process in which molecules are labeled (or tagged) with ubiquitin and directed to cellular machines that break them down. USP13 is known as a de-ubiquitinating enzyme, which removes ubiquitin tags from protein. USP13 renders parkin ineffective via removal of ubiquitin tags (de-ubiquitination) from proteins. Loss of parkin function leads to genetically inherited forms of Parkinson's disease.
The study began with postmortem autopsies of individuals who donated their brains to research, including 11 with Parkinson's disease and a control group of 9 without Parkinson's. The autopsies, which occurred 4 to 12 hours after death, found that the level of USP13 was significantly increased in the midbrain in Parkinson's disease patients, compared to the control participants. Studies in mouse models of Parkinson's disease then demonstrated that knocking out the USP13 gene increased alpha-synuclein ubiquitination and destruction. Researchers also saw that USP13 knockdown protected the mice against alpha-synuclein-induced dopamine neuron death. The mice had improved motor performance; parkin protein was increased and alpha-synuclein was cleared.
Report of success in PD animal models by targeting NLRP3 activation:
https://www.genengnews.com/news/parkinsons-disease-drug-that-cools-brains-on-fire-could-enter-human-trials-in-2020/
Apparently the drug used, MCC950, works great at nanomolar amounts, but because it's off-patent, the researchers want to develop a *new* drug. So there's a highly effective drug for Parkinson's but because it's off-patent it can't be tested in clinical trials since no one can make any money on it...