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SMG1 identified as a regulator of Parkinson's disease-associated alpha-synuclein through siRNA screening
SMG1 identified as a regulator of Parkinson's disease-associated alpha-synuclein through siRNA screening
- Source :
- PLoS ONE, Vol 8, Iss 10, p e77711 (2013), PLoS ONE
- Publication Year :
- 2013
- Publisher :
- Public Library of Science (PLoS), 2013.
-
Abstract
- Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129) compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson’s disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn). Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD). These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.
- Subjects :
- Lewy Body Disease
Parkinson's disease
Hyperphosphorylation
Down-Regulation
lcsh:Medicine
Biology
Protein Serine-Threonine Kinases
Poly(A)-Binding Proteins
03 medical and health sciences
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
0302 clinical medicine
mental disorders
medicine
Humans
Phosphorylation
RNA, Small Interfering
lcsh:Science
Cells, Cultured
030304 developmental biology
Synucleinopathies
Alpha-synuclein
0303 health sciences
Multidisciplinary
Kinase
Dementia with Lewy bodies
lcsh:R
Brain
Parkinson Disease
medicine.disease
Cell biology
T-Cell Intracellular Antigen-1
nervous system diseases
chemistry
Biochemistry
nervous system
Synuclein
alpha-Synuclein
Dementia
lcsh:Q
Tumor Suppressor Protein p53
030217 neurology & neurosurgery
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 8
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....f3e14d8373f8fdfabd5058d7538c5ec3