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Targeting ?-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies.

ABSTRACT: Reducing the burden of ?-synuclein oligomeric species represents a promising approach for disease-modifying therapies against synucleinopathies such as Parkinson's disease and dementia with Lewy bodies. However, the lack of efficient drug discovery strategies that specifically target ?-synuclein oligomers has been a limitation to drug discovery programs.Here we describe an innovative strategy that harnesses the power of bimolecular protein-fragment complementation to monitor synuclein-synuclein interactions. We have developed two robust models to monitor ?-synuclein oligomerization by generating novel stable cell lines expressing ?-synuclein fusion proteins for either fluorescent or bioluminescent protein-fragment complementation under the tetracycline-controlled transcriptional activation system.A pilot screen was performed resulting in the identification of two potential hits, a p38 MAPK inhibitor and a casein kinase 2 inhibitor, thereby demonstrating the suitability of our protein-fragment complementation assay for the measurement of ?-synuclein oligomerization in living cells at high throughput.The application of the strategy described herein to monitor ?-synuclein oligomer formation in living cells with high throughput will facilitate drug discovery efforts for disease-modifying therapies against synucleinopathies and other proteinopathies.

SUBMITTER: Moussaud S

PROVIDER: S-EPMC4608017 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Targeting α-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies.

Moussaud Simon S Malany Siobhan S Mehta Alka A Vasile Stefan S Smith Layton H LH McLean Pamela J PJ

Expert opinion on therapeutic targets 20150318 5

<h4>Objective</h4>Reducing the burden of α-synuclein oligomeric species represents a promising approach for disease-modifying therapies against synucleinopathies such as Parkinson's disease and dementia with Lewy bodies. However, the lack of efficient drug discovery strategies that specifically target α-synuclein oligomers has been a limitation to drug discovery programs.<h4>Research design and methods</h4>Here we describe an innovative strategy that harnesses the power of bimolecular protein-fr ...[more]

PMID: 25785645

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Project description:Parkinson's disease (PD), multiple system atrophy (MSA) and Dementia with Lewy bodies (DLB) represent pathologically similar, progressive neurodegenerative disorders characterized by the pathological aggregation of the neuronal protein α-synuclein. PD and DLB are characterized by the abnormal accumulation and aggregation of α-synuclein in proteinaceous inclusions within neurons named Lewy bodies (LBs) and Lewy neurites (LNs), whereas in MSA α-synuclein inclusions are mainly detected within oligodendrocytes named glial cytoplasmic inclusions (GCIs). The presence of pathologically aggregated α-synuclein along with components of the protein degradation machinery, such as ubiquitin and p62, in LBs and GCIs is considered to underlie the pathogenic cascade that eventually leads to the severe neurodegeneration and neuroinflammation that characterizes these diseases. Importantly, α-synuclein is proposed to undergo pathogenic misfolding and oligomerization into higher-order structures, revealing self-templating conformations, and to exert the ability of "prion-like" spreading between cells. Therefore, the manner in which the protein is produced, is modified within neural cells and is degraded, represents a major focus of current research efforts in the field. Given that α-synuclein protein load is critical to disease pathogenesis, the identification of means to limit intracellular protein burden and halt α-synuclein propagation represents an obvious therapeutic approach in synucleinopathies. However, up to date the development of effective therapeutic strategies to prevent degeneration in synucleinopathies is limited, due to the lack of knowledge regarding the precise mechanisms underlying the observed pathology. This review critically summarizes the recent developed strategies to counteract α-synuclein toxicity, including those aimed to increase protein degradation, to prevent protein aggregation and cell-to-cell propagation, or to engage antibodies against α-synuclein and discuss open questions and unknowns for future therapeutic approaches.

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Dataset Information

Targeting ?-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies.

Publications

Targeting α-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies.

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