Small, aggregated proteins capable of entering cells have been shown to cause distinctive toxic effects in Parkinson’s disease and dementia with Lewy bodies, according to a new study led by Dr Yu Ye (UK DRI at Imperial).
The findings, published in the journal Proceedings of the National Academy of Sciences (PNAS), offer useful insight into the underlying mechanisms of these diseases, and highlight potential future targets for disease detection and therapeutic intervention.
Both Parkinson’s disease and dementia with Lewy bodies are associated with abnormal deposits or ‘aggregates’ of a protein called alpha-synuclein in the brain. The protein accumulates in different sized structures, from small, soluble entities to larger fibre-like structures known as ‘fibrils’.
Increasing evidence suggests that the small soluble aggregates are more toxic to cells than the larger fibrils. However, small aggregates are more difficult to detect within live cells and brain tissue, and are therefore more challenging to characterise and quantify.
In this study, Dr Ye’s team aimed to provide insight into how small aggregates damage cells in neurodegenerative diseases. Using a specialist microscope, and a fluorescent ‘tag’ to label the aggregate, they showed it was possible to precisely detect and measure small protein aggregates in live cells and mouse brain tissue.
The study revealed that protein aggregates below a certain size (450 nanometres) entered cells more easily, whereas larger aggregates were prevented from entering by the plasma membrane, the barrier that separates the interior of a cell from the outside environment.