The small aromatic compound SynuClean-D inhibits the aggregation and seeded polymerization of multiple α-synuclein strains

2022-04-04 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​The small aromatic compound SynuClean-D inhibits the aggregation and seeded polymerization of multiple α-synuclein strains​
Peña-Díaz, S.; Pujols, J.; Vasili, E.; Pinheiro, F.; Santos, J.; Manglano-Artuñedo, Z. & Outeiro, T. F.  et al.​ (2022) 
The Journal of Biological Chemistry, art. 101902​.​ DOI: https://doi.org/10.1016/j.jbc.2022.101902 

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Authors
Peña-Díaz, Samuel; Pujols, Jordi; Vasili, Eftychia; Pinheiro, Francisca; Santos, Jaime; Manglano-Artuñedo, Zoe; Outeiro, Tiago F. ; Ventura, Salvador
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, as well as the accumulation of intra-neuronal proteinaceous inclusions known as Lewy bodies and Lewy neurites. The major protein component of Lewy inclusions is the intrinsically disordered protein α-Synuclein (α-Syn), which can adopt diverse amyloid structures. Different conformational strains of α-Syn have been proposed to be related to the onset of distinct synucleinopathies; however, how specific amyloid fibrils cause distinctive pathological traits is not clear. Here, we generated three different α-Syn amyloid conformations at different pH and salt concentrations and analyzed the activity of SynuClean-D (SC-D), a small aromatic molecule, on these strains. We show that incubation of α-Syn with SC-D reduced the formation of aggregates and the seeded polymerization of α-Syn in all cases. Moreover, we found that SC-D exhibited a general fibril disaggregation activity. Finally, we demonstrate that treatment with SC-D also reduced strain-specific intracellular accumulation of phosphorylated α-Syn inclusions. Taken together, we conclude that SC-D may be a promising hit compound to inhibit polymorphic α-Syn aggregation.
Issue Date
4-April-2022
Journal
The Journal of Biological Chemistry 
Project
EXC 2067: Multiscale Bioimaging 
SFB 1286: Quantitative Synaptologie 
Working Group
RG Outeiro (Experimental Neurodegeneration) 
ISSN
0021-9258
eISSN
1083-351X
Language
English

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