Biology subjects

Parente, M.

Publications and source records attributed to Parente, M..

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↗

bioRxiv2023

Non-indigenous seaweeds in the Northeast Atlantic Ocean, the Mediterranean Sea and Macaronesia: a critical synthesis of diversity, spatial and temporal patterns

Effective monitoring and combatting the effect of non-indigenous seaweeds relies on a solid confirmation of the non-indigenous status of the species. We critically analysed the status of presumed non-indigenous seaweed species reported from the Mediterranean Sea, the Northeast Atlantic Ocean and Macaronesia, resulting in a list of 140 species whose non-indigenous nature is undisputed. For an additional 87 species it is unclear if they are native or non-indigenous (cryptogenic species) or their identity requires confirmation (data deficient species). We discuss the factors underlying both taxonomic and biogeographic uncertainties and outline recommendations to reduce uncertainty about the non-indigenous status of seaweeds. Our dataset consisted of over 19,000 distribution records, half of which can be attributed to only five species (Sargassum muticum, Bonnemaisonia hamifera, Asparagopsis armata, Caulerpa cylindracea and Colpomenia peregrina), while 56 species (40%) are recorded no more than once or twice. In addition, our analyses revealed considerable variation in the diversity of non-indigenous species between the geographic regions. The Eastern Mediterranean Sea is home to the largest fraction of non-indigenous seaweed species, the majority of which have a Red Sea or Indo-Pacific origin and have entered the Mediterranean Sea mostly via the Suez Canal. Non-indigenous seaweeds with native ranges situated in the Northwest Pacific make up a large fraction of the total in the Western Mediterranean Sea, Lusitania and Northern Europe, followed by non-indigenous species with a presumed Australasian origin. Uncertainty remains, however, regarding the native range of a substantial fraction of non-indigenous seaweeds in the study area. In so far as analyses of first detections can serve as a proxy for the introduction rate of non-indigenous seaweeds, these do not reveal a decrease in the introduction rate, indicating that the current measures and policies are insufficient to battle the introduction and spread of non-indigenous species in the study area. HighlightsO_LINon-indigenous seaweed species in the Northeast Atlantic Ocean, the Mediterranean Sea and Macaronesia are critically reanalysed. C_LIO_LI>19,000 distribution records revealed considerable variation in diversity of non-indigenous seaweed species in the study area. C_LIO_LITaxonomic and biogeographic uncertainties hamper a critical evaluation of the non-indigenous status of many seaweed species. C_LI

plant biology↗