Dr. Geoffrey Hesketh, Post-doctoral fellow
Lunenfeld-Tanenbaum Research Institute
Mount Sinai Hospital/University of Toronto
Basic Research Fellowship: $100,000, 2 years

Mass spectrometry-based characterization of protein trafficking proteins implicated in Parkinson’s disease pathogenesis

The beauty of basic research is that sometimes, when you’re not looking for it, you make a discovery that answers a critical question in an entirely different field.

That’s what happened to Geoffrey Hesketh. Hesketh, a cell biologist, was investigating how proteins move around in cells to arrive at their surface in the correct order required to do their jobs. He was concentrating on the Retromer proteins, a group of proteins that work together to pick transport proteins from their starting point to the correct spots that allow them to send and receive communications signals.

Other researchers had already figured out that damaged forms of one particular protein in the group – a protein called VPS35 – lead to Parkinson’s disease. Hesketh’s work revealed that nine other genes associated with Parkinson’s disease are also part of the Retromer group. That discovery points to this group of proteins as being critical players in the cause of Parkinson’s disease.

Now Hesketh, who has switched the focus of his project to Parkinson’s, uses a technique called mass spectrometry to screen all the proteins in the Retromer group. He wants to identify all the proteins they communicate with, because they could also be implicated in Parkinson’s disease.

The next step for researchers is to figure out how and why, when things go wrong in the Retromer group, Parkinson’s disease results. One theory is that any defect in the Retromer pathway results in fewer proteins getting to the right spots on the surface of brain cells. That could disrupt communication among the cells. Cells that produce dopamine – the chemical in the brain that affects movement – could be more susceptible to this disruption.

“Or it just could be that after losing their connections with the neighbouring cells, these cells (with damaged Retromer proteins) just shrivel up and die,” Hesketh says.

Knowing exactly what goes wrong at the cellular level is critical for the design of any future drug to treat Parkinson’s, says Hesketh.

He is passionate about the need for basic research and its unintended
consequences, rather than only funding research with direct medical or industrial
applications.

“You can sometimes learn much more about a disease process when you don’t even know
you are studying that disease in the first place,” he says. “I think I’m a good example of that.”