Understanding the molecular basis of α-synuclein strain interference

Researchers have identified the protein implicated in the death of the brain cells that cause Parkinson’s: alpha-synuclein.

What researchers don’t understand, however, is why clumps, or aggregates, of alpha-synuclein accumulating in brain cells are also implicated in Multiple System Atrophy (MSA), and dementia with Lewy bodies.

“The same protein that aggregates in all these different disorders results in different clinical profiles and symptoms,” says Surabhi Mehra, a neuroscientist and post-doctoral fellow at the University of Toronto.

Mehra will spend the next two years trying to decipher the properties of alpha-synuclein that allow it to exhibit this chameleon-type behaviour.

She’s working on the hypothesis that alpha-synuclein behaves like another class of proteins known as prions. This would mean alpha-synuclein acts as an infectious molecule that can travel from one region of the brain to another and evolve into different strains, causing different diseases.

“These prion-like strains are not static and they may evolve into each other or may exist as a dynamic cloud of strains, which complicates strategies to develop a drug against them,” Mehra says.

She will mix different strains of alpha-synuclein together, derived from tissue samples from people with Parkinson’s and MSA, and study them in cell cultures and animal models.

She’s trying to determine how different strains evolve, and how they block or interfere with one another.

She hopes to discover how this single protein develops the code that enables it to evolve into these different strains.

Understanding how these molecular pathways work could reveal new strategies for how to block the spread of the protein or the evolution of different strains.

“This study will provide a research roadmap, for developing a cocktail of drugs or individual drug therapies,” Mehra says.

Currently, everyone with Parkinson’s receives the same drug (levodopa) to treat the illness. If doctors knew how people acquired Parkinson’s , they could develop individual treatment plans, she says.

“We will open a window to better understanding and potential treatment of all these disorders,” she says.

Mehra has long felt an urgent need to help find better treatment or a cure for people with Parkinson’s, inspired by her uncle’s long illness.

“He was not treated well. It always motivated me,” she says.

Basic research, including this project, is essential to designing drugs that could eventually help people like Mehra’s uncle, she says.

“If we know the root cause, we know what to target,” she adds.