Towards a new understanding of Parkinson’s disease

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parkinsonsParkinson’s disease (PD) is the second most common neurodegenerative disease (after Alzheimer’s disease) affecting between seven to 10 million people worldwide. While treatments exist, there is no cure and the cause of the disease in most patients is still not understood.

Researchers have looked at proteins mutated in genetic forms of the disease in order to get a better understanding of the origin of PD. These studies have identified damaged mitochondria as a cause of PD. Mitochondria – the energy power plants of cells – require the proteins, Parkin and PINK1, to avoid accumulating damage over time.  Now, a new study from McGill Faculty of Medicine researchers published in the latest edition of The EMBO Journal sheds light on how one of these key proteins works to protect us from PD.

“Starting about 10 years ago, researchers realized that PINK1 and Parkin function together as a quality control system to maintain healthy mitochondria,” says McGill’s Dr. Véronique Sauvé, lead author of the study.  “Both proteins are necessary to protect neurons and ensure their long-term survival. Mutations in either one lead to Parkinson’s disease.”

The team of researchers from McGill’s Faculty of Medicine, led by Dr. Kalle Gehring and Dr. Jean-François Trempe, previously described the 3D shape of a quiescent, inactive form of Parkin.  “How the two proteins work together has been controversial and actively researched,” notes Gehring.  “We published the structure of an inactive conformation of Parkin in Science two years ago. Building on that study, many groups around the world are studying how PINK1 switches Parkin into an active form.”

In the current study, the McGill researchers have identified a protein switch in Parkin that converts it from an inactive to active form. The researchers observed that Parkin is normally off and waiting for PINK1 to identify damaged mitochondria. In a two-step process, PINK1 marks damaged mitochondria with phosphorylated ubiquitin molecules and then modifies Parkin to switch it to the active conformation. Working together PINK1 and Parkin remove damaged components from mitochondria and maintain healthy neurons. “The mechanism of Parkin activation is of broad interest,” says Sauvé. “These studies deepen our understanding of genetic mutations that cause PD and provide a canvas for the development of new therapies to slow or prevent the progression of other, non-genetic forms of Parkinson’s disease.”

 Read the article here

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