Early α-synuclein–mediated mitochondrial dysfunction in a human cell model of Parkinson’s disease dementia
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.
Authors
- Johan Jakobsson (ORCID: https://orcid.org/0000-0003-0669-7673)
- Jana Šebestíková (ORCID: https://orcid.org/0000-0002-4821-1232)
- Maria Grazia Spillantini (ORCID: https://orcid.org/0000-0002-8544-7332)
- Wei‐Li Kuan (ORCID: https://orcid.org/0000-0002-0273-1320)
- Raquel Garza (ORCID: https://orcid.org/0000-0002-2524-3055)
- Kornélia Szebényi (ORCID: https://orcid.org/0000-0003-1558-8372)
- Shaline V. Fazal (ORCID: https://orcid.org/0000-0002-2813-4022)
- Xiaoling He (ORCID: https://orcid.org/0009-0004-1002-8418)
- Maha S. Alfaidi (ORCID: https://orcid.org/0009-0006-1380-9935)
- Thomas B. Stoker
- Léa M. D. Wenger
- Amir Jassim
- Roger A. Barker (ORCID: https://orcid.org/0000-0001-8843-7730)
- Richard J. Gilbertson (ORCID: https://orcid.org/0000-0001-7539-9472)
Institutions
- Lund University (SE)
- MRC Cognition and Brain Sciences Unit (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Cancer Research UK (GB)
- Cancer Research UK Cambridge Center (GB)
- Institute of Materials and Environmental Chemistry (HU)
- Alzheimer’s Research UK (GB)
- Drug Discovery Laboratory (Norway) (NO)
- Addenbrooke's Hospital (GB)
- Research Network (United States) (US)
- HUN-REN Research Centre for Natural Sciences (HU)
Publication Details
- Journal
- Communications Biology
- Published
- 2026-05-12
- DOI
- https://doi.org/10.1038/s42003-026-10134-x
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Saudi Arabia Cultural Bureau in London
- Lunds Universitet