Convergent transcriptomic signature in iPSC-dopaminergic neurons of hereditary Parkinson's disease

Abstract

The clinical and genetic diversity of Parkinson's disease (PD) makes it challenging to identify common mechanisms across different forms. To search for such shared pathways, we performed transcriptomic analysis of iPSC-derived dopaminergic neurons from patients with LRRK2 or Parkin mutations. We discovered a convergent gene expression signature in both genetic backgrounds, indicating a shift away from developmental and proliferative programs (e.g., Wnt/β-catenin signaling, cell cycle) and toward pathways of mature neuronal function (e.g., synaptic transmission, potassium channels). This shift was particularly pronounced in LRRK2 neurons, which showed enhanced markers of synaptic maturation. Concurrently, PD neurons exhibited down-regulation of gene programs supporting axon growth and structural development and upregulated TRAIL (TNF-related apoptosis-inducing ligand) apoptotic pathway. Our findings suggest that in these hereditary forms of PD, distinct mutations may propel neurons toward a similar state of premature specialization coupled with impaired structural development and increased vulnerability, revealing a potential common path in disease pathogenesis.

Abstract of "Convergent transcriptomic signature in iPSC-dopaminergic neurons of hereditary Parkinson's disease" by Kopylova IV, Ivanov AB, Eidelman LR et al., https://doi.org/10.26508/lsa.202503551, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.