Abstract
Cerebral palsy (CP) comprises a group of non-progressive neurodevelopmental disorders characterized by motor impairment and often accompanied by intellectual disability, epilepsy, and sensory deficits. While historically attributed to birth asphyxia, recent genomic research has revealed that many CP cases have a genetic basis. This project focuses on mutations in the KIF1A, AP-4, and KLC4 genes, which converge on a shared defect in ATG9A trafficking, disrupting neuronal autophagy, an essential process for maintaining neuronal health and connectivity. Using patient-derived and genome-edited iPSC-based neuronal models, we will elucidate how impaired ATG9A transport affects neuronal morphology, synaptic function, and network activity. Multi-modal analyses including live-cell imaging, patch-clamp electrophysiology, and multi-electrode array recordings will identify cellular phenotypes linking defective intracellular transport to neuronal dysfunction. We will then test pharmacological compounds—Rapamycin, Carbamazepine, and Tubastatin A—that activate autophagy or enhance axonal transport, assessing their ability to restore neuronal and network function. This project represents the first integrative attempt to mechanistically unify genetically diverse forms of CP under a common pathway involving autophagy and vesicular transport defects. By bridging molecular and functional evidence across multiple genetic etiologies, it aims to shift the current paradigm of CP from perinatal hypoxia toward defined, targetable cellular mechanisms, laying the groundwork for precision medicine approaches for affected children.
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