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Neurodegenerative diseases are thought to be caused by the accumulation of toxic protein aggregates. For example, aggregates of a protein called α-synuclein cause diseases known as α-synucleinopathies, which include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. But how do aggregates of one particular protein cause three different diseases with different toxicities and symptoms? Genjiro Suzuki, a senior scientist in the Dementia Research Project has been studying this problem and recently published his work in a paper, “α-synuclein strains that cause distinct pathologies differentially inhibit proteasome,” eLife 2020;9:e56825. We spoke to him about his work.
What research problems are you studying?
I’m interested in understanding the propagation of neurodegenerative diseases. In most neurodegenerative diseases, degeneration starts in a particular area of the brain and gradually spreads to other areas. I want to understand how this spread occurs. Neurodegerative diseases are associated with protein aggregation in the brain. Different diseases are associated with aggregation of different proteins such as α-synuclein, TDP-43, or tau. For example, a class of diseases known as α-synucleinopathies, which include dementia with Lewy bodies, Parkinson’s disease, and multiple system atrophy, is thought to be caused by aggregation of α-synuclein. How does aggregation of one protein cause three different diseases? This is one of the questions that I am studying.
What is the prion hypothesis?
One model for how protein aggregates spread throughout the brain is the prion hypothesis. Prions are proteins that can form different shapes or conformations. Some conformations are soluble and non-infectious, while others are harmful and can form aggregates. Prion proteins in harmful conformations can bind to prion proteins in soluble conformations and shift them to the harmful conformation. This causes the spread of harmful proteins and these proteins get transferred to other cells to spread the disease to other regions of the brain. Currently we believe that neurodegenerative diseases spread throughout the brain in a process similar to the propagation of prion aggregates.
What are the new findings in your eLife paper?
If three different α-synucleinopathies are all caused by aggregation of α-synuclein, it’s possible that α-synuclein can form at least three different aggregate structures, each corresponding to a different α-synucleinopathy. My work supports this idea. I first purified soluble α-synuclein and then aggregated this protein under different salt conditions to show that different aggregates are formed with different characteristics. This work shows how aggregation of one protein might cause different diseases with different symptoms and toxicities.
How is the toxicity of aggregates related to inhibition of the proteasome?
Old, damaged or deleterious proteins are degraded by the proteasome. Thus proteasomal activity is critical for cells. I found that more toxic α-synuclein aggregates inhibited proteasomal activity while less toxic aggregates did not. This suggests that the toxicity of aggregates may be related to their ability to inhibit proteasomal activity.
What is the significance of your work?
Overall, my work shows that proteins associated with neurodegenerative diseases can adopt several different conformations. These different conformations can have different effects on cell functions. This helps explain how different neurodegenerative diseases can have different severities and different rates of spread.
How do you plan to continue this work?
The α-synuclein aggregates we made in vitro are structurally different from aggregates found in disease patients. One of my future plans is to make in vitro aggregates that are very close to those found in disease patients. This would allow us to analyze how disease aggregates inhibit proteasome activity. It would also be very useful in screening studies to develop new treatments for these diseases.
Are non-toxic aggregates found in people, and do you think they could be used to treat diseases?
I don’t think α-synuclein aggregates have been found in people without neurodegeneration, but there are reports of accumulation of tau aggregates in people without neurodegeneration. So maybe Alzheimer’s patients have tau aggregates that are toxic and inhibit the proteasome, while healthy older people can have tau aggregates that aren’t toxic and might even function protectively. It would be fascinating if we could make non-toxic protein aggregate seeds that we could use to inhibit the formation of toxic aggregates.