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α-Synuclein molecular behavior and nigral proteomic profiling distinguish subtypes of Lewy body disorders

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Abstract

Lewy body disorders (LBD), characterized by the deposition of misfolded α-synuclein (α-Syn), are clinically heterogeneous. Although the distribution of α-Syn correlates with the predominant clinical features, the burden of pathology does not fully explain the observed variability in clinical presentation and rate of disease progression. We hypothesized that this heterogeneity might reflect α-Syn molecular diversity, between both patients and different brain regions. Using an ultra-sensitive assay, we evaluated α-Syn seeding in 8 brain regions from 30 LBD patients with different clinical phenotypes and disease durations. Comparing seeding across the clinical phenotypes revealed that hippocampal α-Syn from patients with a cognitive-predominant phenotype had significantly higher seeding capacity than that derived from patients with a motor-predominant phenotype, whose nigral-derived α-Syn in turn had higher seeding capacity than that from cognitive-predominant patients. Interestingly, α-Syn from patients with rapid disease progression (< 3 years to development of advanced disease) had the highest nigral seeding capacity of all the patients included. To validate these findings and explore factors underlying seeding heterogeneity, we performed in vitro toxicity assays, and detailed neuropathological and biochemical examinations. Furthermore, and for the first time, we performed a proteomic-wide profiling of the substantia nigra from 5 high seeder and 5 low seeder patients. The proteomic data suggests a significant disruption in mitochondrial function and lipid metabolism in high seeder cases compared to the low seeders. These observations suggest that distinct molecular populations of α-Syn may contribute to heterogeneity in phenotypes and progression rates in LBD and imply that effective therapeutic strategies might need to be directed at an ensemble of differently misfolded α-Syn species, with the relative contribution of their differing impacts accounting for heterogeneity in the neurodegenerative process.

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Acknowledgements

The authors particularly acknowledge the patients and their families for their donation. We would also like to acknowledge Dr. Michael Ford and MS Bioworks for their support with the mass spectrometry. Figure 3a was designed with BioRender.com.

Funding

This study was supported by the Edmond J. Safra Philanthropic Foundation, the Krembil Foundation, the Rossy Foundation, the Maybank Foundation (to G.G.K. and A.E.L.), the Blidner Family Foundation (to N.P.V.), the Canadian Foundation for Innovation (CFI) John R. Evans Leaders Fund (40480) and the Ontario Research Fund for Small Infrastructure Funds (to G.G.K.). E.S. and J.F.-I. were supported by a grant from the Spanish Ministry of Science Innovation and Universities (Ref. PID2019-110356RB-I00/AEI/10. 13039/501100011033). The funding bodies did not take part in design of the study, in collection, analysis, or interpretation of data, or in writing the manuscript.

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  1. Paulina Gonzalez-Latapi

    Present address: Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Authors and Affiliations

  1. Tanz Centre for Research in Neurodegenerative Disease (CRND), University of Toronto, Krembil Discovery Tower, 60 Leonard Ave, Toronto, ON, M5T 0S8, Canada

    Ivan Martinez-Valbuena, Valerie Sackmann, Ain Kim, Jun Li, Naomi P. Visanji, Anthony E. Lang & Gabor G. Kovacs

  2. Edmond J. Safra Program in PD and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, ON, Canada

    Emily Swinkin, Paulina Gonzalez-Latapi, Greg Kuhlman, Suvorit Subhas Bhowmick, Naomi P. Visanji, Anthony E. Lang & Gabor G. Kovacs

  3. Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdisNa), Pamplona, Spain

    Enrique Santamaria & Joaquin Fernandez-Irigoyen

  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Ain Kim, Naomi P. Visanji, Anthony E. Lang & Gabor G. Kovacs

  5. Krembil Brain Institute, University Health Network, Toronto, ON, Canada

    Naomi P. Visanji & Gabor G. Kovacs

  6. Laboratory Medicine Program, University Health Network, Toronto, ON, Canada

    Gabor G. Kovacs

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Gabor G. Kovacs is member of the Acta Neuropathologica Editorial Board but was not involved in the editorial handling of this article. GGK holds a shared patent for the 5G4 synuclein antibody.

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Martinez-Valbuena, I., Swinkin, E., Santamaria, E. et al. α-Synuclein molecular behavior and nigral proteomic profiling distinguish subtypes of Lewy body disorders. Acta Neuropathol 144, 167–185 (2022). https://doi.org/10.1007/s00401-022-02453-0

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