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Endogenous Levels of Alpha-Synuclein Modulate Seeding and Aggregation in Cultured Cells

Lookup NU author(s): Professor Tiago OuteiroORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2022, The Author(s). Parkinson’s disease is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alpha-synuclein in intraneuronal inclusions known as Lewy bodies and Lewy neurites. Multiple studies strongly implicate the levels of alpha-synuclein as a major risk factor for the onset and progression of Parkinson’s disease. Alpha-synuclein pathology spreads progressively throughout interconnected brain regions but the precise molecular mechanisms underlying the seeding of alpha-synuclein aggregation are still unclear. Here, using stable cell lines expressing alpha-synuclein, we examined the correlation between endogenous alpha-synuclein levels and the seeding propensity by exogenous alpha-synuclein preformed fibrils. We applied biochemical approaches and imaging methods in stable cell lines expressing alpha-synuclein and in primary neurons to determine the impact of alpha-synuclein levels on seeding and aggregation. Our results indicate that the levels of alpha-synuclein define the pattern and severity of aggregation and the extent of p-alpha-synuclein deposition, likely explaining the selective vulnerability of different cell types in synucleinopathies. The elucidation of the cellular processes involved in the pathological aggregation of alpha-synuclein will enable the identification of novel targets and the development of therapeutic strategies for Parkinson’s disease and other synucleinopathies.

Publication metadata

Author(s): Vasili E, Dominguez-Meijide A, Flores-Leon M, Al-Azzani M, Kanellidi A, Melki R, Stefanis L, Outeiro TF

Publication type: Article

Publication status: Published

Journal: Molecular Neurobiology

Year: 2022

Volume: 59

Pages: 1273–1284

Print publication date: 01/02/2022

Online publication date: 04/01/2022

Acceptance date: 22/12/2021

Date deposited: 01/02/2022

ISSN (print): 0893-7648

ISSN (electronic): 1559-1182

Publisher: Springer

URL: https://doi.org/10.1007/s12035-021-02713-2

DOI: 10.1007/s12035-021-02713-2

Data Access Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

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