CHARACTERIZATION OF NOGO-A–MEDIATED MECHANISMS UNDERLYING DOPAMINERGIC AND MITOCHONDRIAL DYSREGULATION IN AN IPSC-DERIVED PARKINSON’S DISEASE MODEL

Nogo-A, a myelin-associated protein, was demonstrated to inhibit axonal regeneration, thus limiting the ability for repair within the central nervous system. Its involvement in synaptic regulation, myelin maintenance, and mitochondrial homeostasis has raised interest in its role in Parkinson’s disease (PD). In particular, understanding Nogo-A’s multifaceted role in the involvement of dopaminergic neuronal survival may provide insights into PD pathophysiology and potential therapeutic targets.
We examined the effects of Nogo-A on neuronal development and neurodegeneration using wild-type (WT) and Nogo-A knockout (KO) human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons. To model PD-related stress, cells were exposed to 6-hydroxydopamine (6-OHDA). Viability, oxidative stress, mitochondrial function, and electrophysiology were assessed using proteomics, qPCR, functional assays, and high-density multi-electrode array (HD-MEA).
6-OHDA treatment reduced cell viability and increased oxidative stress across both genotypes. Nogo-A KO cultures exhibited a higher basal proportion of tyrosine hydroxylase (TH)-positive cells, suggesting enhanced dopaminergic differentiation. Nogo-A-KO neurons displayed a significant upregulation of dopaminergic markers, including TH and LMX1A, although survival rates following 6-OHDA were comparable between genotypes. Preliminary results show that Nogo-A-KO neurons exhibited higher baseline superoxide levels; however, their functional mitochondria parameters diverged from those of WT neurons under stress conditions.
These findings suggest that Nogo-A influences dopaminergic homeostasis and mitochondrial dynamics. The observed differences in KO cells highlight the complex role of Nogo-A and warrant further investigation regarding the underlying molecular pathways for stress response modulation.