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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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, 2020. "Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy," Nature, Nature, vol. 578(7794), pages 273-277, February.
    • Handle: RePEc:nat:nature:v:578:y:2020:i:7794:d:10.1038_s41586-020-1984-7
    DOI: 10.1038/s41586-020-1984-7
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    Citations

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    Cited by:

    1. Vishruth Mullapudi & Jaime Vaquer-Alicea & Vaibhav Bommareddy & Anthony R. Vega & Bryan D. Ryder & Charles L. White & Marc. I. Diamond & Lukasz A. Joachimiak, 2023. "Network of hotspot interactions cluster tau amyloid folds," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Nicholas H. Stillman & Johnson A. Joseph & Jemil Ahmed & Charles Zuwu Baysah & Ryan A. Dohoney & Tyler D. Ball & Alexandra G. Thomas & Tessa C. Fitch & Courtney M. Donnelly & Sunil Kumar, 2024. "Protein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson’s phenotypes," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    3. Jemil Ahmed & Tessa C. Fitch & Courtney M. Donnelly & Johnson A. Joseph & Tyler D. Ball & Mikaela M. Bassil & Ahyun Son & Chen Zhang & Aurélie Ledreux & Scott Horowitz & Yan Qin & Daniel Paredes & Sun, 2022. "Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Simone Bido & Sharon Muggeo & Luca Massimino & Matteo Jacopo Marzi & Serena Gea Giannelli & Elena Melacini & Melania Nannoni & Diana Gambarè & Edoardo Bellini & Gabriele Ordazzo & Greta Rossi & Camill, 2021. "Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Youqi Tao & Yunpeng Sun & Shiran Lv & Wencheng Xia & Kun Zhao & Qianhui Xu & Qinyue Zhao & Lin He & Weidong Le & Yong Wang & Cong Liu & Dan Li, 2022. "Heparin induces α-synuclein to form new fibril polymorphs with attenuated neuropathology," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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