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An old mystery solved: New findings change our understanding of the course of Parkinson's disease

Researchers at the Walter and Eliza Hall Institute (WEHI) in Melbourne have solved a long-standing mystery regarding the role of a protein in removing damaged mitochondria from the body. These findings may pave the way for potential new treatments for Parkinson's disease

Cellular "garbage bags" are built using optineurin (in green) around damaged mitochondria (in red). Credit: WEHI
Cellular "garbage bags" are built using optineurin (in green) around damaged mitochondria (in red). Credit: WEHI

Researchers at the Walter and Eliza Hall Institute (WEHI) in Melbourne have solved a long-standing mystery regarding the role of a protein in removing damaged mitochondria from the body. These findings may pave the way for potential new treatments for Parkinson's disease.

Mitochondria play a critical role in producing the energy our cells need to perform their various functions, but when it is damaged it can greatly affect cell function and contribute to the development of various diseases.

Abnormal mitochondria are normally eliminated and recycled through a garbage disposal process called mitophagy.

PINK1 and Parkin are two proteins that are essential for this process, they are responsible for "tagging" dysfunctional mitochondria for destruction. In Parkinson's, mutations in these proteins can cause a build-up of damaged mitochondria in the brain, which can lead to motor symptoms such as tremors, stiffness and difficulty moving.

The new study, published in Molecular Cell, solves a mystery about how the protein optineurin recognizes damaged mitochondria that have been "tagged" by PINK1 and parkin, and enables their transfer to the body's waste disposal system.

Dr. Tan Nuan (left) and Prof. Hever Michael Lazaro (right).
Credit: WEHI

Associate Professor Michael Lazaro, Laboratory Director in WEHI's Ubiquitin Marking Division, said the discovery filled a vital knowledge gap that would transform our understanding of this cellular pathway. "Until this study, the exact role of optineurin in the body's waste disposal process was unknown."

"There are many proteins that bind damaged cellular materials to the waste disposal mechanism, but we found that optineurin does this in a very unusual way that is unlike anything else we have seen in similar proteins.

"This discovery is important because the human brain relies on optineurin to destroy the mitochondria through the waste disposal system using PINK1 and Parkin. If we know how optineurin does this, we will have a framework that will allow us to possibly target PINK1 and Parkin mitophagy in the disease and prevent the accumulation of damaged mitochondria in neurons with age.

"If we succeed, it will be of great importance to people with Parkinson's - a disease that continues to affect more than ten million people worldwide, including 80,000 Australians."

PINK1 works inside the mitochondria and is responsible for monitoring its state. When it detects problems, it activates parkin, which tags damaged mitochondria for disposal.

They work together and instruct our body to create cellular "garbage bags" around damaged mitochondria and enlist the help of optineurin to start this process.

In the new study, it was discovered that optineurin eliminates damaged mitochondria by binding to an enzyme called TBK1. From there, it was found that TBK1 in turn activates a specific cellular machinery that has a key role in creating these garbage bags around damaged mitochondria.

First author Dr. Thanh Nuan said: "Other proteins do not need TBK1 to help them cause this deletion process, so optineurin is truly unusual when it comes to how the body removes mitochondria.

"This allowed us to think about the properties of this pathway involving TBK1 as a potential drug target, and this is a significant step forward in our search for new Parkinson's treatments.

"The ultimate goal will be to find a way to increase the levels of PINK1/Parkin mitophagy in the body - especially in the brain - to more efficiently eliminate damaged mitochondria

"We also hope to design a molecule that can mimic what optineurin does, so that damaged mitochondria can be eliminated even without PINK1 or parkin."

for the scientific article

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