FRET-Based Screening Identifies p38 MAPK and PKC Inhibition as Targets for Prevention of Seeded α-Synuclein Aggregation
(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.
(Less)
- author
- organization
-
- Neural Plasticity and Repair (research group)
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- NanoLund: Centre for Nanoscience
- Chemical Biology and Therapeutics (research group)
- Experimental Dementia Research (research group)
- Centre for Analysis and Synthesis
- Molecular Neuromodulation (research group)
- publishing date
- 2021-07-13
- 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
- 2024-09-21 22:42:30
@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}}, }