The small aromatic compound SynuClean-D inhibits the aggregation and seeded polymerization of multiple α-synuclein strains
Peña Díaz, Samuel (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Pujols Pujol, Jordi (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Vasili, Eftychia (Max Planck Institute for Experimental Medicine)
Pinheiro, Francisca (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Santos, Jaime (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Manglano-Artuñedo, Zoe (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Outeiro, Tiago Fleming (Scientific Employee With a Honorary Contract. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE))
Ventura, Salvador (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")

Data:	2022
Resum:	Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, as well as the accumulation of intraneuronal 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.
Ajuts:	Agencia Estatal de Investigación PID2019-105017RB-I00
Nota:	Altres ajuts: ICREA (ICREA-Academia 2015 and 2020); Fundació la Marató de TV3 (20144330)
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Strains ; Aggregation inhibitor ; Small molecule ; Amyloid structures ; Dopaminergic neurons ; Intrinsically disordered proteins ; Lewy bodies ; Neurites ; Neurodegenerative disorders ; Protein components ; Seeded polymerization ; Substantia nigra ; α-synuclein ; Alpha-synuclein ; Amyloid ; Humans ; Lewy Bodies ; Parkinson Disease ; Polymerization ; Synucleinopathies
Publicat a:	Journal of biological chemistry, Vol. 298, Issue 5 (May 2022) , art. 101902, ISSN 1083-351X

DOI: 10.1016/j.jbc.2022.101902
PMID: 35390347

11 p, 2.5 MB

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