Super-resolution microscopy of alpha-synuclein aggregates in brain samples indicates a subset of cells have disrupted protein homeostasis

Small-soluble aggregates of alpha-synuclein has been observed in Parkinson's disease (PD). However, the processes that occur in-vivo leading to the formation of these aggregates are not well understood. We used sensitive single-molecule methods including SIMOA and super-resolution microscopy to quantify and characterise alpha-synuclein aggregates harvested from human brain samples alongside the Line 61 mouse model using different tissue processing methods. Different sub-populations of aggregates were accessible by different extraction methods and larger aggregates were detected in older mice and PD brain, although the aggregate number did not change significantly in younger mice and controls, respectively. In the mice there was a substantial population of larger (150 nm), fibrillar aggregates, while in PD this population of larger aggregates (100 nm) was only slightly greater than the controls. Our data suggests that alpha-synuclein aggregates slowly in the brain, leading to formation of larger aggregates in a sub-set of cells.