Biology subjects

Pallottini, V.

Publications and source records attributed to Pallottini, V..

4 recordsLinked to original sources

bioRxiv2026

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 patient-specific neuronal model by differentiating induced pluripotent stem cells (iPSCs) carrying the most common NPC1 p.I1061T variant into cortical neurons. These cells exhibit hallmarks of neuronal pathology associated with NPC1 disease, providing a platform to investigate pathological mechanisms and to validate therapeutic candidates in a human context. Using this experimental model, we explored the effects of pharmacological inhibition of bromodomain and extraterminal (BET) proteins. Treatment with the BET inhibitor JQ1 attenuated disease-associated phenotypes, improving neuronal viability and modulating intracellular cholesterol accumulation. Overall, our findings identify BET inhibition as a novel strategy to ameliorate NPC1-associated neuronal pathology and uncover a previously underexplored link between epigenetic regulation and cholesterol homeostasis, highlighting iPSC-derived neurons as a powerful platform for therapeutic discovery.

neuroscience↗

bioRxiv2026

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

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.

neuroscience↗

bioRxiv2023

Reversal of pathologic changes in fibroblasts from Niemann-Pick type C disease patients by inhibition of bromodomain and extraterminal proteins

Inborn errors of lysosomal function often provoke disorders presenting highly variable onset, diverse visceral, neurologic and psychiatric symptoms and reduced life spans. A prime example is Niemann-Pick type C disease (NPCD). At present, therapeutic options are limited to palliative care and disease-modifying drugs, and there is a need for new treatments. Here, we explored bromodomain and extra-terminal domain (BET) proteins as a new drug target for NPCD using patient-derived skin fibroblasts. Treatment of cells with JQ1, a prototype BET protein inhibitor, enhanced the level of NPC1 protein, diminished lysosomal expansion and cholesterol accumulation, and induced extracellular release of lysosomal components in a dose- and time-dependent manner. The effect of JQ1 on protein levels was largely independent from the patient line tested, but the extent of cholesterol reduction varied in a line-dependent manner. Lastly, JQ1 enhanced and reduced cholesterol accumulation induced by inhibition of NPC1 activity and of histone deacetylases, respectively. Taken together, our results provide further evidence for epigenetic regulation of cellular NPC1 levels and cholesterol homeostasis. Pharmacologic inhibition of bromodomain proteins should be explored as candidate therapeutic approach for NPCD and as a tool to understand basic mechanisms of lysosomal function and lipid metabolism.

cell biology↗

bioRxiv2021

Glial contribution to cyclodextrin-mediated reversal of cholesterol accumulation in murine NPC1-deficient neurons in vivo

Niemann-Pick type C (NPC) disease is a rare and fatal lysosomal storage disorder presenting severe neurovisceral symptoms. Disease-causing mutations in genes encoding either NPC1 or NPC2 protein provoke accumulation of cholesterol and other lipids in specific structures of the endosomal-lysosomal system and degeneration of specific cells, notably neurons in the central nervous system (CNS). 2-hydroxypropyl-beta-cyclodextrin (CD) emerged as potential therapeutic approach based on animal studies and clinical data, but the mechanism of action on neurons has remained unclear. To address this topic in vivo, we took advantage of the retina as highly accessible part of the (CNS) and intravitreal injections as mode of drug administration. We find that CD enters the endosomal-lysosomal system of neurons and enables the release of lipid-laden lamellar inclusions, which are then removed from the extracellular space by specific types of glial cells. Thus, CD triggers a concerted action of neurons and glial cells to restore lipid homeostasis in the central nervous system.

neuroscience↗