Endogenous levels of alpha-synuclein modulate seeding and aggregation in cultured cells

Eftychia Vasili (1) , Antonio Dominguez-Meijide (1, 2) , Manuel Flores-León (3) , Mohammed Al-Azzani (1) , Angeliki Kanellidi (4) , Ronald Melki (5, 6) , Leonidas Stefanis (4) , Tiago Outeiro (1, 4, 7, 8)

1 Department of Experimental Neurodegeneration [Göttingen, Germany]
2 USC - Universidade de Santiago de Compostela [Spain]
3 UNAM - Universidad Nacional Autónoma de México = National Autonomous University of Mexico
4 BRFAA - Biomedical Research Foundation of the Academy of Athens
5 CEA - CEA- Saclay
6 MIRCEN - Molecular Imaging Research Center [Fontenay-aux-Roses]
7 Newcastle University [Newcastle]
8 DZNE Göttingen

Parkinson's disease is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alphasynuclein 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.

Mots clés: PD; LBs; aSyn; Aggregation; Phosphorylation; PD

Domaines: Neurobiologie

Eftychia Vasili, Antonio Dominguez-Meijide, Manuel Flores-León, Mohammed Al-Azzani, Angeliki Kanellidi, et al.. Endogenous levels of alpha-synuclein modulate seeding and aggregation in cultured cells. Molecular Neurobiology, 2021, 59, pp.1273 - 1284. ⟨10.1007/s12035-021-02713-2⟩. ⟨cea-03683738⟩