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Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia.

Overview

Authors: Maha S Alfaidi1,2, Léa M D Wenger1,2, Kornélia Szebényi1,3, Thomas B Stoker1,2, Xiaoling He1, Shaline V Fazal1, Jana Sebestikova2, Amir Jassim4, Richard J Gilbertson4,5, Raquel Garza6,7, Johan Jakobsson6,7, Maria Grazia Spillantini2, Roger A Barker1,2,6,8,9,10, Wei-Li Kuan8
ORCID iDs: Maha S Alfaidi, Kornélia Szebényi, Xiaoling He, Richard J Gilbertson, Raquel Garza, Roger A Barker, Wei-Li Kuan
  1. John van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK
  2. Department of Clinical Neurosciences, Cambridge University, Cambridge, UK
  3. Research Centre of Natural Sciences, Institute of Molecular Life Sciences, Budapest, Hungary
  4. Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, UK
  5. Department of Oncology, University of Cambridge, The Early Cancer Institute, Cambridge, UK
  6. Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD USA
  7. Department of Experimental Medical Science, Wallenberg Neuroscience Centre and Lund Stem Cell Centre, BMC A11, Lund University, Lund, Sweden
  8. ALBORADA Drug Discovery Institute, Cambridge, UK
  9. Department of Neurology, Addenbrooke’s Hospital, Cambridge, UK
  10. Cambridge Stem Cell Centre, Cambridge, UK
Institutions: University of Cambridge (United Kingdom); Institute of Molecular Life Sciences (Hungary); Cancer Research UK (United Kingdom); Lund University (Sweden); Aligning Science Across Parkinson's (United States); Wellcome/MRC Cambridge Stem Cell Institute (United Kingdom); Addenbrooke's Hospital (United Kingdom)
Journal: Communications biology, volume 9, issue 1, article 1098
Dates: received 30 June 2025; accepted 16 April 2026; published online 12 May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s42003-026-10134-x · PMID 42120738 · PMCID PMC13470013 · OpenAlex W7160891111
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), Alzheimer's / dementia (population), Parkinson's (population), cellular / molecular (subfield)
Methods: Statistics, Connectivity, Single-unit activity, calcium imaging
Keywords: Cellular neuroscience, Parkinson's disease, Experimental models of disease, Neural ageing
MeSH: alpha-Synuclein*, Dementia*, Mitochondria*, Neurons*, Parkinson Disease*, Cells, Cultured, Humans (* major topic)
Topic: Parkinson's Disease Mechanisms and Treatments (Neurology, Medicine), according to OpenAlex
Funding: Saudi Arabia Cultural Bureau in London (Royal Embassy of Saudi Arabia Cultural Bureau in London) (G102704)
Citations: cited by 1 paper (Europe PMC); 40 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Code availability

No custom code was developed for this study. All figures and statistical analyses were generated using IBM SPSS Statistics Version 29.0 and GraphPad Prism Version 9.4.1. scRNA-seq data were analysed using established workflows in Seurat (versions 3.1/4.0.1), following publicly available tutorials.

Reproduced under the paper's license (CC BY), from the paper cited above.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

Data availability

Raw single-cell RNA sequencing (scRNA-seq) data generated in this study are deposited in ArrayExpress (EMBL-EBI) under accession number E-MTAB-16863 (https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-MTAB-16863). Differential gene expression lists, including statistical outputs and normalised expression values, are provided in the Supplementary Data (Excel file). All remaining data supporting the findings of this study are contained within the manuscript and its Supplementary Materials.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 4 keywords, 7 MeSH terms, 1 funder, 37 references.

Cite

This paper

Alfaidi, M. S., Wenger, L. M. D., Szebényi, K., Stoker, T. B., He, X., Fazal, S. V., Sebestikova, J., Jassim, A., Gilbertson, R. J., Garza, R., Jakobsson, J., Spillantini, M. G., Barker, R. A., & Kuan, W.-L. (2026). Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia. Communications biology, 9(1), 1098. https://doi.org/10.1038/s42003-026-10134-x

BibTeX

@article{alfaidi2026early,
author = {Alfaidi, Maha S and Wenger, Léa M D and Szebényi, Kornélia and Stoker, Thomas B and He, Xiaoling and Fazal, Shaline V and Sebestikova, Jana and Jassim, Amir and Gilbertson, Richard J and Garza, Raquel and Jakobsson, Johan and Spillantini, Maria Grazia and Barker, Roger A and Kuan, Wei-Li},
title = {{Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia}},
journal = {Communications biology},
year = {2026},
month = may,
volume = {9},
number = {1},
pages = {1098},
publisher = {Nature Publishing Group},
issn = {2399-3642},
doi = {10.1038/s42003-026-10134-x},
url = {https://doi.org/10.1038/s42003-026-10134-x},
pmid = {42120738},
pmcid = {PMC13470013}
}

RIS

TY - JOUR
AU - Alfaidi, Maha S
AU - Wenger, Léa M D
AU - Szebényi, Kornélia
AU - Stoker, Thomas B
AU - He, Xiaoling
AU - Fazal, Shaline V
AU - Sebestikova, Jana
AU - Jassim, Amir
AU - Gilbertson, Richard J
AU - Garza, Raquel
AU - Jakobsson, Johan
AU - Spillantini, Maria Grazia
AU - Barker, Roger A
AU - Kuan, Wei-Li
TI - Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia
T2 - Communications biology
J2 - Commun Biol
PY - 2026
DA - 2026/05/12
VL - 9
IS - 1
SP - 1098
SN - 2399-3642
PB - Nature Publishing Group
DO - 10.1038/s42003-026-10134-x
UR - https://doi.org/10.1038/s42003-026-10134-x
LA - en
ER -

CSL-JSON

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