PhD defence Y. Zhang

The role of SK channels in neurodegeneration

Focus on neuronal differentiation, ferroptosis, and neuroprotection

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by amyloid β (Aβ) deposits and neurofibrillary tangles (NFTs). Emerging research links ferroptosis, a form of neuronal death, to AD, even before clinical symptoms arise. Human iPSC-based models allow exploration of early AD mechanisms, revealing that Presenilin 1 (PSEN1) mutations drive premature neuronal differentiation prior to Aβ and tau aggregation. Small conductance calcium-activated potassium (SK) channels, particularly SK2 and SK3, are implicated in ferroptosis, excitotoxicity, and early differentiation in AD. Our research demonstrates that SK2 channel activators reduce ferroptosis and excitotoxicity by restoring mitochondrial function and calcium levels. Newly identified potent SK2 activators showed stronger neuroprotective effects than commercial compounds CyPPA and NS309, with potential therapeutic implications. In iPSC-derived neuronal progenitors from AD patients with PSEN1 mutations, SK3 channels were highly expressed, correlating with premature neuronal differentiation marked by enhanced calcium signaling, ER-mitochondrial contacts, and altered morphology. Pharmacological SK channel activation further amplified differentiation by regulating neurogenesis genes, underscoring their role in premature-related AD pathogenesis. Beyond neurodegeneration and differentiation, SK channels influence glioma progression in the review. SK channel activation enhances glioblastoma cell death through mitochondrial disruption. In gliomas, IK (SK4) overexpression correlates with advanced stages and poorer survival, while its activation in immune cells shows therapeutic promise. Our findings reveal SK channels as pivotal regulators in neurodegenerative and oncological contexts, offering novel therapeutic targets for AD and gliomas.