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E. Glaab

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Aug 2026

Integrative Multi-Omics Analysis Reveals Convergent Epigenome and Transcriptome Changes in Parkinson's Disease.

BACKGROUND The mechanisms that predispose dopaminergic neurons (DAN) to degeneration in Parkinson's disease (PD) are incompletely understood. OBJECTIVE To perform an integrative multi-omics reanalysis of single-cell transcriptomic and epigenomic data to identify convergent alterations predisposing dopaminergic neurons to degeneration in Parkinson's disease, and to generate new bulk ATAC-seq profiles from peripheral monocytes to assess whether these alterations extend to a systemic, cross-tissue epigenetic signature. METHODS We reanalyzed single-cell RNA sequencing (scRNA-seq; n = 27 PD, 11 controls) and single-cell ATAC sequencing (scATAC-seq; n = 10 PD, 2 controls) data from induced pluripotent stem cell (iPSC)-derived DANs (Foundational Data Initiative for Parkinson's Disease [FOUNDIN-PD]) to identify convergent transcriptional and epigenetic alterations. We generated new bulk ATAC-seq from peripheral monocytes of parkinsonian disorder patients (n = 10) and controls (n = 4) to assess cross-tissue epigenetic signatures. RESULTS Convergent downregulation in neurodevelopmental and synaptic pathways was observed across neuronal maturation stages. Network perturbation analysis identified SMARCA4 as a key upstream regulator. Monocyte comparison revealed 44 genes with concordant chromatin accessibility changes, with NFATC2 exhibiting decreased accessibility across all neuronal subtypes and monocytes. CONCLUSION This exploratory analysis identifies shared transcriptomic-epigenomic alterations at gene, pathway, and network levels in PD neurons and preliminary systemic epigenetic signatures that warrant validation in larger cohorts. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mirco Macchi, A. Ginolhac, Tony Heurtaux et al. · 0 citations
Open access Aug 2026

LRRK2-G2019S impairs astrocyte differentiation and triggers a senescence-like phenotype in Parkinson’s disease models

Astrocytes are increasingly recognised as essential contributors to both physiological brain function and neurodegenerative diseases. Here, we describe how the Parkinson’s disease (PD)-associated mutation LRRK2-G2019S affects astrocytes using autoptic brain samples and PD patient-specific 3D midbrain organoids and 2D astrocytes derived from induced pluripotent stem cells. In autoptic midbrain samples from LRRK2-G2019S patients, we observed a reduction in GFAP⁺ astrocytes but increased branching, together with transcriptional signatures consistent with altered astrocyte function. We also observed delayed astrocyte differentiation in PD patient-specific midbrain organoids, accompanied by altered astrocyte transcriptomic profiles revealed by single-cell RNA sequencing. This defective differentiation contributes to the acquisition of a senescent-like phenotype. In 2D cultures, astrocyte differentiation from LRRK2-G2019S precursor cells was associated with early apoptosis and altered Wnt/β-catenin and TGFβ signalling compared to LRRK2-WT cultures. Notably, pharmacological activation of the developmental transcription factor NR2F1, downregulated in LRRK2-G2019S models, reduced astrocyte cell death and senescence-like phenotypes. Together, these data show that LRRK2-G2019S impairs astrocyte specification and predisposes to a senescent phenotype.

Lisa M. Smits, S. Magni, K. Grzyb et al. · 0 citations