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Alpha-synuclein fragments trigger distinct aggregation pathways.
Chakroun, Tasnim; Evsyukov, Valentin; Nykänen, Niko-Petteri; Höllerhage, Matthias; Schmidt, Andreas; Kamp, Frits; Ruf, Viktoria C; Wurst, Wolfgang; Rösler, Thomas W; Höglinger, Günter U.
Afiliación
  • Chakroun T; Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 81377, Munich, Germany.
  • Evsyukov V; Munich Cluster for Systems Neurology (SyNergy), University of Munich, 81377, Munich, Germany.
  • Nykänen NP; Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 81377, Munich, Germany.
  • Höllerhage M; Department of Neurology, School of Medicine, Technical University of Munich, 81675, Munich, Germany.
  • Schmidt A; Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 81377, Munich, Germany.
  • Kamp F; Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 81377, Munich, Germany.
  • Ruf VC; Department of Neurology, School of Medicine, Technical University of Munich, 81675, Munich, Germany.
  • Wurst W; Protein Analysis Unit (ZfP), Biomedical Center (BMC), University of Munich, 82152, Planegg, Germany.
  • Rösler TW; Metabolic Biochemistry, Biomedical Center (BMC), University of Munich, 81733, Munich, Germany.
  • Höglinger GU; Center for Neuropathology and Prion Research, University of Munich, 81733, Munich, Germany.
Cell Death Dis ; 11(2): 84, 2020 02 03.
Article en En | MEDLINE | ID: mdl-32015326
Aggregation of alpha-synuclein (αSyn) is a crucial event underlying the pathophysiology of synucleinopathies. The existence of various intracellular and extracellular αSyn species, including cleaved αSyn, complicates the quest for an appropriate therapeutic target. Hence, to develop efficient disease-modifying strategies, it is fundamental to achieve a deeper understanding of the relevant spreading and toxic αSyn species. Here, we describe comparative and proof-of-principle approaches to determine the involvement of αSyn fragments in intercellular spreading. We demonstrate that two different αSyn fragments (1-95 and 61-140) fulfill the criteria of spreading species. They efficiently instigate formation of proteinase-K-resistant aggregates from cell-endogenous full-length αSyn, and drive it into different aggregation pathways. The resulting aggregates induce cellular toxicity. Strikingly, these aggregates are only detectable by specific antibodies. Our results suggest that αSyn fragments might be relevant not only for spreading, but also for aggregation-fate determination and differential strain formation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fragmentos de Péptidos / Alfa-Sinucleína / Agregación Patológica de Proteínas Límite: Humans Idioma: En Revista: Cell Death Dis Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fragmentos de Péptidos / Alfa-Sinucleína / Agregación Patológica de Proteínas Límite: Humans Idioma: En Revista: Cell Death Dis Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido