Synucleinopathies are
neurodegenerative diseases that are associated with the misfolding and aggregation of α-
synuclein, including
Parkinson's disease,
dementia with Lewy bodies and multiple system atrophy1. Clinically, it is challenging to differentiate
Parkinson's disease and
multiple system atrophy, especially at the early stages of disease2. Aggregates of α-
synuclein in distinct
synucleinopathies have been proposed to represent different conformational strains of α-
synuclein that can self-propagate and spread from cell to cell3-6.
Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect α-
synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity7,8. Here we show that the α-
synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with
Parkinson's disease and samples from patients with
multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and
biological methods to analyse the product of α-
synuclein-PMCA, and found that the characteristics of the α-
synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between
Parkinson's disease and
multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that α-
synuclein aggregates that are associated with
Parkinson's disease and
multiple system atrophy correspond to different conformational strains of α-
synuclein, which can be amplified and detected by α-
synuclein-PMCA. Our results may help to improve our understanding of the mechanism of α-
synuclein misfolding and the structures of the aggregates that are implicated in different
synucleinopathies, and may also enable the development of a biochemical assay to discriminate between
Parkinson's disease and
multiple system atrophy.