Effects of bromodomain and extraterminal domain protein inhibition in a mouse model of Niemann-Pick type C disease

Parente, M.; Barthelemy, A.; Caputo, S.; Charlery-Adele, N.; Tonini, C.; Prtvar, D.; Tahirovic, S. W.; Reibel, S.; Pfrieger, F. W.; Pallottini, V.

doi:10.64898/2026.06.24.734200

bioRxiv · 10.64898/2026.06.24.734200

Effects of bromodomain and extraterminal domain protein inhibition in a mouse model of Niemann-Pick type C disease

Parente, M.·Barthelemy, A.·Caputo, S.·Charlery-Adele, N.·Tonini, C.·Prtvar, D.·Tahirovic, S. W.·Reibel, S.·Pfrieger, F. W.·Pallottini, V.

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Abstract

Defects in lysosomal lipid handling provoke fatal disorders presenting neurovisceral symptoms with variable onset and life spans. A prime example is Niemann-Pick type C disease (NPCD), where export of cholesterol and other lipids from the endosomal-lysosomal system is impaired due to variants of either NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2). Therapeutic options for NPCD are limited to palliative care and disease-modifying drugs, and there is an unmet need for new treatments. Based on positive effects in patient-derived fibroblasts in vitro, we explored how inhibition of bromodomain and extra-terminal domain (BET) proteins affects a well-established mouse model bearing the frequent I1061T variant of NPC1. Treatment with JQ1, a hydrophobic prototype BET protein inhibitor, induced beneficial but sex-dependent molecular and behavioral changes in mice. Our results indicate bromodomain proteins as therapeutic drug target for NPCD and reveal sex-dependent BET protein signaling in mice.

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Parente, M., Barthelemy, A., Caputo, S., Charlery-Adele, N., Tonini, C., Prtvar, D., Tahirovic, S. W., Reibel, S., Pfrieger, F. W., Pallottini, V.. 2026-06-29. Effects of bromodomain and extraterminal domain protein inhibition in a mouse model of Niemann-Pick type C disease. https://doi.org/10.64898/2026.06.24.734200

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