Parkinson’s disease (PD) is the fastest-growing neurodegenerative disorder, with no disease-modifying therapeutics currently available. The selective vulnerability of dopaminergic (DA) neurons in the substantia nigra pars compacta remains poorly understood. Using LUHMES-derived human DA neurons, we show that these cells are acutely sensitive to mitochondrial apoptosis and ferroptosis, but relatively resistant to inflammatory cell death pathways such as pyroptosis and necroptosis. Live-cell imaging and viability assays reveal that DA neurons are highly susceptible to inhibition of the pro-survival protein BCL-XL, suggesting they are primed for mitochondrial apoptosis.
CRISPR-mediated knockout of the pro-apoptotic effector BAX confers strong protection against DA neuron death induced by BCL-XL inhibitor or mitochondrial toxins, identifying BAX as a critical vulnerability node. To explore therapeutically tractable strategies for modulating BAX, we employed a PROTAC-based degradation approach. Using the dTAG system, we achieved efficient degradation of FKBP12F36V-BAX with two targeted degrader compounds dTAGV-1 or dTAG-13 resulting in marked protection of DA neurons from apoptosis.
While the brain penetrance of these compounds remains to be established, recent studies have demonstrated the feasibility of CNS-targeted protein degradation, supporting the broader therapeutic potential of this approach. These findings provide compelling proof-of-concept for modulating mitochondrial apoptosis in DA neurons via selective protein degradation and highlight PROTAC technology as a promising avenue for developing disease-modifying therapies in PD.