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Insights into Parkinson’s disease

Just as your parcels are packaged and delivered to your doorstep, so your body has molecular machines responsible for packaging cellular cargo and ensuring it gets to the correct location within the cell. However, just as parcel delivery can go wrong, so it can in your body. Misdelivered cellular cargo can lead to devastating neurodegenerative diseases such as Parkinson’s disease.

An international team led by A/Prof. Brett Collins from the University of Queensland (UQ), Dr John Briggs at MRC Laboratory of Molecular Biology (LMB), UK, and Prof. David Owen at Cambridge Institute for Medical Research, UK have joined with collaborators at the Max Planck Institute of Biochemistry, Germany, to solve the structure of retromer, the molecular machine responsible for ensuring the safe and efficient transport of cellular cargo.

Retromer consists of four proteins bound to the membrane surrounding a cellular compartment called an endosome. It is found in species from baker’s yeast to humans and controls molecular sorting – redirecting incoming molecules to where they need to go.

Recently, the team determined the 3D structure of the entire yeast retromer complex in its assembled, membrane-bound state. Cryo-electron microscopy on frozen samples enabled the intricate details of the protein structures to be elucidated.

A number of microscopy techniques in Microscopy Australia’s UQ facility complimented other results from the LMB. Results revealed that three of the retromer proteins form a supportive network of arches that are docking points for control proteins. In cooperation with membrane-associated sorting proteins, they cause the membrane to bend and form tubules. It is these tubules that deliver the cargo around the cell. The structure shows that a mutation known to cause Parkinson’s disease might interfere with how the arches interact with each other.

This work will allow scientists to better understand how mutations in retromer lead to neurodegeneration and potentially provide a basis for designing drugs to help treat the disease.

Kovtun, O., Leneva, N., Bykov, Y. S., Ariotti, N., Teasdale, R. D., Schaffer, M., Engel, B. D., Owen, D. J., Briggs, J., & Collins, B. M. (2018). Structure of the membrane-assembled retromer coat determined by cryo-electron tomography. Nature561(7724), 561–564.

July 24, 2018