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

Svanbergsson, Alexander LU orcid ; Ek, Fredrik LU ; Martinsson, Isak LU ; Rodo, Jordi ; Liu, Di LU ; Brandi, Edoardo LU ; Haikal, Caroline LU ; Torres-Garcia, Laura LU ; Li, Wen LU and Gouras, Gunnar LU orcid , et al. (2021) In Neurotherapeutics 18(3). p.1692-1709
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neurotherapeutics
volume
18
issue
3
pages
1692 - 1709
publisher
Springer
external identifiers
  • scopus:85110712889
  • pmid:34258749
ISSN
1878-7479
DOI
10.1007/s13311-021-01070-1
language
English
LU publication?
yes
id
5cb46f7d-6c9a-4e08-be8e-801935608d69
date added to LUP
2021-07-23 12:58:27
date last changed
2024-06-15 13:40:56
@article{5cb46f7d-6c9a-4e08-be8e-801935608d69,
  abstract     = {{<p>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.</p>}},
  author       = {{Svanbergsson, Alexander and Ek, Fredrik and Martinsson, Isak and Rodo, Jordi and Liu, Di and Brandi, Edoardo and Haikal, Caroline and Torres-Garcia, Laura and Li, Wen and Gouras, Gunnar and Olsson, Roger and Björklund, Tomas and Li, Jia-Yi}},
  issn         = {{1878-7479}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{3}},
  pages        = {{1692--1709}},
  publisher    = {{Springer}},
  series       = {{Neurotherapeutics}},
  title        = {{FRET-Based Screening Identifies p38 MAPK and PKC Inhibition as Targets for Prevention of Seeded α-Synuclein Aggregation}},
  url          = {{http://dx.doi.org/10.1007/s13311-021-01070-1}},
  doi          = {{10.1007/s13311-021-01070-1}},
  volume       = {{18}},
  year         = {{2021}},
}