Parkinson's Disease is a chronic neurodegenerative disease that causes movement problems in the early stages and progresses over time to affect other things like cognition. The disease has an early onset form, which affects patients before they reach age 50, and is due to genetic mutations; mutations that alter a protein called PINK1 were identified many years ago as a cause of early onset Parkinson's. Scientists have now learned more about how these mutations lead to the disease. The findings, which have been reported in Science, may help researchers develop better treatments for the disorder.
Mitochondria are well known as the powerhouses of cells, and they are crucial to cell function. A gene called PARK6 encodes for the PINK1 protein, which normally works to identify mitochondria that are damaged, and tag them for disposal.
PINK1 proteins gather on damaged mitochondrial membranes, and use a tag known as ubiquitin to signal to the cell that these damaged mitochondria should be removed. If PINK1 is mutated, however, it cannot send that signal, and damaged mitochondria accumulate in cells. These damaged mitochondria seem to cause many problems with neurons that die off in Parkinson's. Brain cells in particular use a lot of energy and carry many mitochondria. As aberrant mitochondria fill certain cells, they die off. Parkinson's is known to be related to the death of dopamine-producing neurons.
Scientists have long known that PINK1 damage is associated with early onset Parkinson's, but this is the first study to reveal how PINK1 attaches to mitochondrial surfaces, and how it gets activated.
This work has revealed that PINK1 identifies damaged mitochondria, binds to them, and attaches ubiquitin, triggering a link to a protein known as Parkin. The damaged mitochondria can then be recycled by the cell. The study found that there are many proteins that work to form a binding site, noted first study author Dr. Sylvie Callegari, a senior researcher at Walter and Eliza Hall Institute (WEHI).
"We also saw, for the first time, how mutations present in people with Parkinson's disease affect human PINK1," noted Callegari.
"This is a significant milestone for research into Parkinson's. It is incredible to finally see PINK1 and understand how it binds to mitochondria," noted corresponding study author Professor David Komander of WEHI. "Our structure reveals many new ways to change PINK1, essentially switching it on, which will be life-changing for people with Parkinson's."
Now the investigators want to find a drug that can help people with mutated PINK1.
Sources: Walter and Eliza Hall Institute, Science
