Dr. Nicholas Silver, University of Toronto
Graduate Student Award, $20,000 over 2 years
Project description:
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.
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 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.