FRET-Based Screening Identifies p38 MAPK and PKC Inhibition as Targets for Prevention of Seeded α-Synuclein Aggregation

Alexander Svanbergsson, Fredrik Ek, Isak Martinsson, Jordi Rodo, Di Liu, Edoardo Brandi, Caroline Haikal, Laura Torres-Garcia, Wen Li, Gunnar Gouras, Roger Olsson, Tomas Björklund, Jia-Yi Li

Research output: Contribution to journalArticlepeer-review

2 Citations (SciVal)

Abstract

Aggregation of α-synuclein is associated with neurodegeneration and a hallmark pathology in synucleinopathies. These aggregates are thought to function as prion-like particles where the conformation of misfolded α-synuclein determines the traits of the induced pathology, similar to prion diseases. Still, little is known about the molecular targets facilitating the conformation-specific biological effects, but their identification could form the basis for new therapeutic interventions. High-throughput screening of annotated compound libraries could facilitate mechanistic investigation by identifying targets with impact on α-synuclein aggregation. To this end, we developed a FRET-based cellular reporter in HEK293T cells, with sensitivity down to 6.5 nM α-synuclein seeds. Using this model system, we identified GF109203X, SB202190, and SB203580 as inhibitors capable of preventing induction of α-synuclein aggregation via inhibition of p38 MAPK and PKC, respectively. We further investigated the mechanisms underlying the protective effects and found alterations in the endo-lysosomal system to be likely candidates of the protection. We found the changes did not stem from a reduction in uptake but rather alteration of lysosomal abundance and degradative capacity. Our findings highlight the value high-throughput screening brings to the mechanistic investigation of α-synuclein aggregation while simultaneously identifying novel therapeutic compounds.

Original languageEnglish
Pages (from-to)1692-1709
JournalNeurotherapeutics
Volume18
Issue number3
Early online date2021 Jul 13
DOIs
Publication statusPublished - 2021

Subject classification (UKÄ)

  • Neurosciences

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