Parkinson's research: message from the cell

Autophagy can be thought of as the "waste disposal system" by which cells cleanse themselves. An elaborate molecular surveillance system identifies broken cell components, clumped proteins or even pathogens and initiates their removal. This prevents cellular "trash" from accumulating. 

Even entire cell organelles can be removed as part of this process. Mitophagy is a form of autophagy in which defective or excess mitochondria are broken down.

Who gives the "trash removal" command?

Disruptions to these processes can have serious consequences, including the development of neurodegenerative diseases. In particular, dysfunctions in mitophagy are associated with Parkinson's disease. To combat Parkinson's disease, it is therefore important to understand the exact molecular processes underlying mitophagy.

Led by postdoctoral researcher Elias Adriaenssens from Sascha Martens' group, researchers from the Max Perutz Labs at the University of Vienna have discovered a new mechanism that triggers mitophagy. 

So far, mitophagy research has been focusing primarily on the "PINK1/Parkin signalling pathway". Signalling pathways transmit information within cells. These complex networks of molecules control critical cellular functions such as growth, division, cell death and also mitophagy. 

"We realised that there were huge gaps in our knowledge beyond PINK1/Parkin," explains study leader Elias Adriaenssens. "Therefore, we decided to investigate signalling pathways which have been largely neglected by researchers. By trying to recreate the signalling pathways in the laboratory, we were able to gain fundamental insights into the mechanisms behind them."

New players in autophagy

To their surprise, the researchers discovered that two known mitophagy receptors can trigger autophagy without binding to the FIP200 protein. FIP200 was previously considered indispensable for triggering autophagy. "That presented us with a conundrum. We asked ourselves how the receptors work without this supposedly crucial protein," says Adriaenssens. 

The researchers found that "WIPI proteins" bind to the receptors. The fact that they are involved in triggering autophagy is a surprising discovery ‒ it was previously assumed that WIPI proteins act only later in the signalling pathway.

Perspectives for Parkinson's research

Subsequent experiments confirmed that this interaction between the receptors and the WIPI proteins is not an exception but may indicate the presence of previously unknown signalling pathways. "This is an exciting discovery that reveals a parallel trigger for selective autophagy. Instead of a single, universal mechanism, cells appear to use different molecular strategies depending on the receptor and context," says Adriaenssens.

The study raises an important question: How do cells decide between alternative mitophagy signalling pathways? Understanding this could pave the way for treatments that specifically activate one signalling pathway to compensate for defects in the other, which has long-term potential for the treatment of Parkinson's disease.