Protein variations may explain Parkinson’s disease differences

20 December 2019

New research by University of Toronto biochemists looks at how protein strains may vary in the brains of those affected by progressive neurodegenerative diseases, such as Parkinson’s disease.

The findings of the research, published in Nature Neuroscience, have important implications for people who are affected by these diseases, and those trying to develop drugs to help them.

Research led by Dr Joel Watts, principal investigator at the University of Toronto’s Tanz Centre for Research in Neurodegenerative Diseases, may provide an explanation for the patient-to-patient variability evident in the diseases.

Watts’ team includes PhD student Raphaella So (Croucher Scholarship 2018), from Hong Kong, and Angus  Lau, one of the co-first authors of their paper. So explained their findings: “Borrowing a concept in the prion field, which studies misfolded protein diseases such as Mad Cow Disease, we think that protein aggregates can misfold into different structures that are called ‘strains’, and these different structures are responsible for the clinical variability we see in patients.”

Previous studies have suggested that alpha-synuclein, the principal pathological hallmark of Parkinson’s disease, exists as different strains in Parkinson’s and multiple system atrophy patients. The research team sought to understand the molecular basis for the differences.

The researchers introduced into mice two structurally different strains of alpha-synuclein – “salt” and “no salt” fibrils. For the former, sodium chloride was added to the mixture used to make the fibril strain. The two strains displayed different physical and biochemical characteristics and, more importantly, behaved differently when injected into the mouse model.

“The salt fibrils were quicker to induce disease than the no salt fibrils, and the resultant brain pathology was clearly different depending on which fibrils the mice were injected with,” So said. “The motor symptoms the mice had were also distinct.

“Our most surprising finding was, perhaps, that the disease non-salt fibril-injected mice developed actually looked a lot like Parkinson’s disease in humans. This fibril strain, which one can easily mass produce in the lab and inject into mice, may offer new insight into how researchers model the human disease in animals, for research and therapeutic testing,” she said.

Ultimately, the goal is to develop testing paradigms for drugs that better reflect the complexity and variability of the human conditions. This would involve patient-specific medicine when designing therapies or clinical trials, with patients better classified based on the type of strain they had.

At the Joel Watts Lab, So is characterising two more fibril strains to see if they induce other forms of disease in mice. Last year, she presented preliminary results at the International Conference on Alzheimer’s and Parkinson’s Diseases in Lisbon, Portugal, and at the Neuroscience 2019 Conference in Chicago, USA.

Raphaella So received her BSc in Biochemistry and Cell Biology from Hong Kong University of Science and Technology. She is pursuing her PhD in Biochemistry at the University of Toronto, studying Parkinson's disease in Dr Joel Watts's prion laboratory. So's research projects revolve around characterising alpha-synuclein protein aggregates, which are common pathological hallmarks among Parkinson's and some rarer neurodegenerative diseases. So received her Croucher Scholarship in 2018.

To view Raphaella So’s Croucher profile, please click here.