Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia.
Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Cambridge, GB · Author affiliation
John van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK. m.alfaidi2@gmail.com.Location evidence
Budapest, HU · Author affiliation
Research Centre of Natural Sciences, Institute of Molecular Life Sciences, Budapest, Hungary.Location evidence
US · Author affiliation · country only
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.Location evidence
Lund, SE · Author affiliation
Department of Experimental Medical Science, Wallenberg Neuroscience Centre and Lund Stem Cell Centre, BMC A11, Lund University, Lund, Sweden.Location evidence
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Original abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the misfolding and accumulation of α-synuclein (α-syn) into pathological aggregates known as Lewy bodies. PD remains incurable, partly due to limited physiologically relevant models that recapitulate human pathology to enable therapeutic development. We developed a novel in vitro PD dementia model using fetal human cortical neurons seeded with α-syn preformed fibrils (PFFs). This model successfully replicates key PD features, including α-syn aggregation and mitochondrial gene dysregulation. Importantly, RNA sequencing revealed significant transcriptomic concordance between our model and PD postmortem tissue, particularly in the downregulation of mitochondrial genes linked to oxidative phosphorylation. We then evaluated two peptide inhibitors, β-syn36D (B36D) and S62. Both peptides demonstrated effective disaggregation of α-syn fibrils, with B36D showing particular promise by reversing PFF-induced functional and transcriptional changes to baseline levels. This human-relevant model captures essential pathological and transcriptomic disease hallmarks as well as demonstrating utility for therapeutic screening of drugs that block α-syn aggregation.