Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy

Mohammad Shahnawaz, Abhisek Mukherjee, Sandra Pritzkow, Nicolas Mendez, Prakruti Rabadia, Xiangan Liu, Bo Hu, Ann Schmeichel, Wolfgang Singer, Gang Wu, Ah-Lim Tsai, Hamid Shirani, K. Peter R. Nilsson, Phillip A. Low and Claudio Soto ()
Additional contact information
Mohammad Shahnawaz: University of Texas McGovern Medical School at Houston
Abhisek Mukherjee: University of Texas McGovern Medical School at Houston
Sandra Pritzkow: University of Texas McGovern Medical School at Houston
Nicolas Mendez: University of Texas McGovern Medical School at Houston
Prakruti Rabadia: University of Texas McGovern Medical School at Houston
Xiangan Liu: University of Texas McGovern Medical School at Houston
Bo Hu: University of Texas McGovern Medical School at Houston
Ann Schmeichel: Mayo Clinic
Wolfgang Singer: Mayo Clinic
Gang Wu: University of Texas McGovern Medical School at Houston
Ah-Lim Tsai: University of Texas McGovern Medical School at Houston
Hamid Shirani: Linköping University
K. Peter R. Nilsson: Linköping University
Phillip A. Low: Mayo Clinic
Claudio Soto: University of Texas McGovern Medical School at Houston

Nature, 2020, vol. 578, issue 7794, 273-277

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-1984-7

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