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by claude@2026-07, 2026-07-05
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This study developed a scalable cellular seeding assay that uses a fluorescent alpha-synuclein reporter and phenotypic screening to evaluate small molecules that target cellular alpha-synuclein seeded aggregation, followed by multiplexed single-cell RNA sequencing. Three alpha-synuclein aggregation inhibitors tested in clinical trials for Parkinson’s disease—minzasolmin, emrusolmin, and EGCG—were profiled, revealing that lipid metabolism and rRNA processing were prominently affected, and that EGCG’s effects were confined to cells with aggregated alpha-synuclein whereas minzasolmin and emrusolmin also altered transcription in cells without aggregated alpha-synuclein. A key limitation is that the work relies on a cellular model of seeded aggregation rather than in vivo disease tissue. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Parkinson’s disease (PD), dementia with Lewy Bodies (DLB) and multiple system atrophy (MSA) are progressive neurodegenerative disorders marked by the pathological aggregation of alpha-synuclein (ɑSyn). Despite significant research efforts, effective therapeutic interventions remain elusive due to limited understanding of the cellular effects of ɑSyn aggregation and propagation. This study presents the development of a scalable cellular seeding assay for screening small molecules targeting cellular ɑSyn seeded aggregation. By leveraging a fluorescent reporter of ɑSyn and phenotypic screening, the assay enables high-throughput evaluation of potential inhibitors in a cellular environment mimicking disease pathology. We evaluated three different αSyn aggregation inhibitors tested in clinical trials for PD: Minzasolmin, Emrusolmin and EGCG and profiled gene expression using multiplexed single cell RNA sequencing in order to examine their distinct effects on cellular pathways associated with ɑSyn overexpression or seeded aggregation. Two cellular activities were prominently affected: lipid metabolism and rRNA processing. Notably, while EGCG effects were confined to cells with aggregated αSyn, Minzasolmin and Emrusolmin also produced transcriptional changes in cells without aggregated αSyn. Each of the compounds tested induced a partial reversal of transcriptional effects resulting from αSyn seeded aggregation. We identified 391 genes that were no longer significantly differentially expressed upon addition of compound, relative to cells with seeded aggregation. This platform bridges phenotypic screening and molecular pathway analysis, providing insights into druggable pathways for synucleinopathies. The molecular signatures identified here can assist in testing and benchmarking future drug discovery leads.
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Abstract
Parkinson’s disease (PD), dementia with Lewy Bodies (DLB) and multiple system atrophy (MSA) are progressive neurodegenerative disorders marked by the pathological aggregation of alpha-synuclein (ɑSyn). Despite significant research efforts, effective therapeutic interventions remain elusive due to limited understanding of the cellular effects of ɑSyn aggregation and propagation. This study presents the development of a scalable cellular seeding assay for screening small molecules targeting cellular ɑSyn seeded aggregation. By leveraging a fluorescent reporter of ɑSyn and phenotypic screening, the assay enables high-throughput evaluation of potential inhibitors in a cellular environment mimicking disease pathology. We evaluated three different αSyn aggregation inhibitors tested in clinical trials for PD: Minzasolmin, Emrusolmin and EGCG and profiled gene expression using multiplexed single cell RNA sequencing in order to examine their distinct effects on cellular pathways associated with ɑSyn overexpression or seeded aggregation. Two cellular activities were prominently affected: lipid metabolism and rRNA processing. Notably, while EGCG effects were confined to cells with aggregated αSyn, Minzasolmin and Emrusolmin also produced transcriptional changes in cells without aggregated αSyn. Each of the compounds tested induced a partial reversal of transcriptional effects resulting from αSyn seeded aggregation. We identified 391 genes that were no longer significantly differentially expressed upon addition of compound, relative to cells with seeded aggregation. This platform bridges phenotypic screening and molecular pathway analysis, providing insights into druggable pathways for synucleinopathies. The molecular signatures identified here can assist in testing and benchmarking future drug discovery leads.
Competing Interest Statement
The authors have declared no competing interest.
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