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 new or 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.
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.
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. (Genes make proteins to perform functions.)
Hesketh is now more than halfway through a two-year, $100,000 Basic Research Fellowship from the Parkinson Canada Research Program to pursue this research at the Lunenfeld-Tanenbaum Research Institute at Mt. Sinai Hospital in Toronto.
At this point, he’s most excited about the discovery of molecular insights into the “membrane targeting” or clumping of alpha-Synuclein (a-Syn), a gene at the very centre of Parkinson’s disease, and long suspected in the formation of Lewy bodies.
“Knowledge of the precise mechanism of a-Syn membrane binding would be of significant value to the Parkinson’s research community and has the potential to lead to new treatments,” says Hesketh.
Another aim of his work is to complete a “BioID,” and mass spectrometry, of all of the genes known to be associated with Parkinson’s disease, about 50 in total – so far. He is collaborating with Drs. Ted Fon and Heidi McBride of the Montreal Neurological Institute at McGill University, who also have relationships with Parkinson Canada. (Dr. Fon is a previous Chair of our Scientific Advisory Board.) He is also investigating with them on how the various genes and their proteins impact the quality of a cell’s mitochondria, its energy source.
Hesketh is passionate about the need for basic research and its unintended consequences. “Parkinson’s found me, rather than the other way around,” he says. “I was looking into a pathway that I was pursuing out of curiosity. After a couple of years, we stumbled upon this connection to Parkinson’s disease that probably never would have been found, if we hadn’t gone down this curiosity-driven path. The discovery provided a new framework to my research.”
He’s a good example of how basic science research expands our knowledge base and can lead to potential new avenues of exploration and possible clinical applications.
“My research aims to characterize the interactions made by Parkinson’s-associated genes with the goal of identifying cell pathways and functions central to the development and progression of Parkinson’s disease. This investigation offers great promise in discovering the fundamental cause of Parkinson’s, and I believe, offers our best shot at ultimately finding a cure.”