Strain-specific Ability of α-synuclein to Influence the Aggregation of Amyloid-β

RESEARCHER: Nicholas Silver 

INSTITUTE: University of Toronto 

PROJECT GRANT: Graduate Student Award, $20,000 over 2 years co-funded by Parkinson Society British Columbia through the Parkinson Canada Research Program.

The underlying cause of Parkinson’s disease (PD) is thought to be the accumulation of abnormal clumps (“aggregates”) of a protein called alpha-synuclein in brain cells. Aggregation of alpha-synuclein in the brain is also thought to be the cause of other neurodegenerative diseases such as Dementia with Lewy Bodies and Multiple System Atrophy (MSA). Collectively, diseases caused by the aggregation of alpha-synuclein are called “synucleinopathies.”  

However, in many people with synucleinopathies, other proteins will also aggregate in their brains. One of the most common secondary proteins to aggregate in synucleinopathies is amyloid-beta. Amyloid-beta is thought to be a major contributing factor to the development of Alzheimer’s disease and, in persons with synucleinopathies, the aggregation of amyloid-beta alongside alpha-synuclein can exacerbate symptoms, worsen prognosis, or contribute to memory deficits. Nicholas Silver’s research project tries to understand the interaction between amyloid-beta aggregates and alpha-synuclein aggregates in synucleinopathies. In particular, he is focusing on determining what influence alpha-synuclein aggregates may have on amyloid-beta aggregation.

Proteins are tiny machines in cells that have specific functions. The function of a protein is related to its specific shape (“structure”). If a protein forms an aggregate, it becomes abnormally shaped, resulting in a loss of its normal function. When alpha-synuclein aggregates, it can adopt multiple different abnormal structures. Each abnormal structure may cause a unique disease, with one structure causing PD and a separate structure causing MSA, for example. Each unique disease-causing structure is called a “strain”. Given that the presence of amyloid-beta varies significantly between synucleinopathies, Nicholas predicted that only specific strains of alpha-synuclein would influence the aggregation of amyloid-beta.  

To test this, he used mice that develop both alpha-synuclein and amyloid-beta aggregates in their brains. In these experiments, he introduced two different strains of alpha-synuclein into the mice. The first strain is similar to the strain that causes MSA in humans, referred to as the MSA-like strain, whereas the second strain has more PD-like properties and is referred to as the PD-like strain. He found that the MSA-like strain reduced the amount of aggregated amyloid-beta in the brains of the mice, while the PD-like strain had no effect on amyloid-beta aggregation. This was confirmed via multiple different methods and was the same in both male and female mice. As predicted, the presence of amyloid-beta aggregation had no impact on the properties of the alpha-synuclein strains themselves.  

There are two important findings from this experiment. The first is that only specific strains of alpha-synuclein impact amyloid-beta aggregation. This could explain the different prevalence rates of amyloid-beta in synucleinopathy patients. For instance, the lower prevalence of amyloid-beta aggregation in MSA could be attributed to the MSA strain impairing amyloid-beta aggregation, similar to what Nicholas observed with the MSA-like strain in mice. The second important finding is that alpha-synuclein aggregation was not impacted by amyloid-beta. In other words, while alpha-synuclein could alter amyloid-beta aggregation under certain conditions, the opposite is not true based on his data.

Nicholas’ findings have two important implications. The first is that if one were to characterize the effect each human disease-causing alpha-synuclein strain has on amyloid-beta aggregation, it may be possible to identify people at high and low risk for developing amyloid-beta pathology, which would alter disease prognosis.  

Secondly, his data suggests that therapies or treatments that target one of these proteins may not affect the other protein. For example, if a therapy were to reduce amyloid-beta aggregates, it would have no effect on alpha-synuclein aggregation. Conversely, if a therapy were to reduce alpha-synuclein aggregates, especially in MSA, it could potentially increase amyloid-beta aggregation. Given that alpha-synuclein aggregation or amyloid-beta aggregation alone are likely sufficient to cause neurodegeneration, targeting only one of these proteins would likely be insufficient to completely stop the disease. This highlights the importance of holistic treatments for synucleinopathies that target the entirety of the underlying causes, instead of a single aspect of the disease.        

Nicholas completed his Bachelor of Science (Honours) in Neuroscience at the University of Alberta, and is currently pursuing a PhD in Biochemistry at the University of Toronto, where he studies Parkinson’s disease. After completing his PhD, he hopes to attend medical school and eventually become a neurologist working directly with individuals living with Parkinson’s disease.

In addition to his academic work, Nicholas is actively involved in graduate student advocacy as the Vice President Academics for the University of Toronto Graduate Students’ Union and as the Chair of the Graduate Students Caucus for the Canadian Federation of Students–Ontario.

This content was published in the Spring 2026 edition of our quarterly magazine, Viewpoints. The content was accurate as of this publication date.