Pharmacological BET Protein Inhibition Reverts Niemann-Pick Type C Disease-Associated Changes in Human iPSC-Derived Cortical Neurons
Niemann-Pick type C1 (NPC1) disease is a fatal lysosomal disorder caused by impaired intracellular cholesterol trafficking, leading to progressive neurodegeneration and premature death. Despite advances in disease modelling, therapeutic development remains limited, partly due to the lack of human neuronal systems that accurately recapitulate disease-relevant phenotypes. Here, we generated a…
Niemann-Pick type C1 disease, a fatal lysosomal disorder, results from impaired cholesterol trafficking within cells, causing progressive neurodegeneration and early death. Generating a patient-specific neuronal model using induced pluripotent stem cells (iPSCs) harboring the most prevalent NPC1 p.I1061T mutation, researchers observed disease-like traits in these cortical neurons. This model proves invaluable for investigating disease mechanisms and evaluating therapeutic prospects in a human context.
Examining the consequences of pharmacologically inhibiting BET proteins, treatment with the BET inhibitor JQ1 mitigated disease-associated symptoms. This led to improved neuronal survival and the regulation of intracellular cholesterol accumulation. In summary, these findings reveal BET inhibition as a promising approach to alleviate NPC1-related neuronal issues and unveil a previously unexplored connection between epigenetic regulation and cholesterol homeostasis.
The utilization of iPSC-derived neurons emerges as a potent platform for discovering new treatments.
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