Transcriptome signatures of human neural stem cells derived from LRRK2 gene therapeutic cells.

The LRRK2 G2019S mutation is known to have a high penetrance rate associated with Parkinson's disease (PD), prevalent across both familial and sporadic PD cases and implicated in neurodegenerative mechanisms. This mutation disrupts several key cellular processes, particularly affecting the endoplasmic reticulum and mitochondrial functions in neural stem cells (NSCs), which are crucial for protein homeostasis and energy metabolism. Although aging is a major risk factor for PD, the complex interplay between LRRK2 G2019S and aging-related cellular dysfunction in NSCs remains poorly understood. In this study, we performed a comprehensive transcriptomic analysis to characterize the temporal transcriptional changes in LRRK2 G2019S-carrying NSCs across sequential passages, resembling cellular aging. BAC DNA-mediated correction of the LRRK2 mutation significantly restored dysregulated cellular processes, including endoplasmic reticulum-associated protein processing, mitochondrial function, and vesicular trafficking pathways, thereby restoring cellular homeostasis in NSCs. Notably, aged NSCs harboring the LRRK2 G2019S mutation exhibited pronounced alterations in epithelial-mesenchymal transition or TGF-β signaling, exacerbating declines in NSC function. Our findings elucidate the molecular mechanisms underlying LRRK2 G2019S-mediated pathogenesis in aging NSCs and highlight the therapeutic potential of genetic correction strategies for PD treatment.