Transcriptomic analysis of iPSC-derived dopaminergic neurons from LRRK2 and Parkin mutation carriers reveals a convergent signature of reduced developmental/Wnt-β-catenin and axon-growth programs, increased synaptic maturation markers, and upregulation of the TRAIL apoptotic pathway.

Highlights shared, targetable pathways (Wnt/β-catenin suppression, impaired structural/axon growth, TRAIL-mediated apoptosis) across hereditary PD forms that generate actionable hypotheses for neuroprotective interventions and biomarker development, though findings are limited to in vitro iPSC…

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.