Biology subjects

Filipponi, C.

Publications and source records attributed to Filipponi, C..

4 recordsLinked to original sources

bioRxiv2026

Peroxisome dynamics during HSV-1 life cycle in human neurons

HSV-1 is increasingly implicated in Alzheimers disease, yet the mechanisms by which it reshapes neuronal metabolism remain incompletely understood. Here, we demonstrate that HSV-1 co-opts peroxisomal biogenesis and lipid metabolic pathways to promote its replication across human neuronal models. In SH-SY5Y cells, infection triggers a marked expansion of the peroxisomal compartment and alters organelle morphology through upregulation of PGC-1 and PEX13/14/19. Pharmacological stimulation of peroxisome proliferation enhances viral production, whereas inhibition of PEX3-PEX19-dependent biogenesis almost completely suppresses infection. Lipidomic profiling reveals a selective increase in peroxisome-derived plasmalogens and sphingolipids, supporting a role for peroxisomes as a metabolic hub for viral envelopment. This remodeling is recapitulated in hiPSC-derived neurons and human brain organoids, where it is strictly dependent on productive replication and re-emerges upon viral reactivation, but not during latency. Collectively, these findings identify peroxisomes as essential replication-permissive organelles exploited by HSV-1 and suggest that recurrent virus-driven peroxisomal and ether-lipid reprogramming may contribute to neuronal vulnerability in neurodegenerative disease.

microbiology↗

bioRxiv2026

A NAPE-LRRK2 metabolic axis controls lysosomal homeostasis in Parkinson's disease

N-acylphosphatidylethanolamines (NAPEs) are atypical glycerophospholipids that accumulate in response to cellular stress, yet their roles beyond serving as precursors of fatty-acid ethanolamines (FAEs) remain largely unexplored. Here, we identify NAPEs as endogenous regulators of leucine-rich repeat kinase 2 (LRRK2), a master controller of lysosomal homeostasis and a genetic driver of Parkinsons disease. We show that increasing NAPE synthesis or blocking their hydrolysis inhibits LRRK2 kinase activity, enhances lysosomal function, and promotes the clearance of -synuclein aggregates. Conversely, cells in which NAPE hydrolysis is enhanced display increased LRRK2 activation and lysosomal dysfunction. Importantly, in induced pluripotent stem cell-derived dopaminergic neurons carrying the LRRK2-G2019S variant, pharmacological inhibition of NAPE-PLD - the enzyme that degrades NAPEs - restores lysosomal activity and favors the clearance of preformed -synuclein fibrils. Together, our findings identify NAPEs as previously unrecognized lipid regulators of LRRK2 signaling and lysosomal function, revealing a metabolic axis with therapeutic potential in Parkinsons disease. TeaserBoosting neuronal NAPEs silences LRRK2 hyperactivity and clears -synuclein: a lipid-based strategy for Parkinsons disease.

cell biology↗

bioRxiv2026

Unconventional Small Molecule MNP-021 Protects Neuronal and Glial Function from Diabetes-Associated Glucotoxicity and Neuroinflammation

BackgroundDiabetes-associated neurodegeneration is amplified by methylglyoxal (MGO)-driven dicarbonyl stress linking hyperglycemia to neuronal insulin resistance and maladaptive neuroinflammation. We tested the neuroprotective activity of MNP-021, a non-electrophilic TRPA1 modulator, in neurons and glial cells in vitro. MethodsSH-SY5Y neurons were pretreated with MNP-021 and challenged with MGO, then profiled by high-content imaging, RNA-seq, Seahorse OCR/ECAR, glycolytic stress assays and AKT/ERK/CREB immunoblotting {+/-} insulin. In parallel, HMC3 glial cells were treated with MNP-021, exposed to LPS/TNF- or A{beta}(25-35) and tested for viability and inflammatory markers by ELISA and qRT-PCR. ResultsMGO increased nucleus-to-cytoplasm area ratio by 49% and dysregulated glucose handling, increasing 2-NBDG uptake by [~]25%, with GLUT1/GLUT4 membrane redistribution; MNP-021 normalized morphology, uptake, and transporter localization without cytotoxicity up to 10 {micro}M. RNA-seq identified 754 MGO-deregulated genes, including ISR/metabolic nodes (GCK, SESN2, PHGDH/PSAT1, PCK2); MNP-021 buffered stress-induced transcription with limited baseline effects, remodeled mitochondrial redox readouts consistent with controlled ROS signaling, while improving mitochondrial content/architecture and blunting stress-evoked compensatory glycolysis. MNP-021 restored pro-survival signaling (pAKT/pERK and nuclear pCREB), including insulin responsiveness during MGO exposure. MNP-021 reduced IL-6/TNF- release while increasing IL-10 and ARG1 ([~]1.9-fold vs LPS/TNF-) in HMC3 glial cells, shifting them toward a pro-resolving IL-10/ARG1 program with reduced A{beta}(25-35)-evoked cytokine release with GLP-1 remaining very low ([≤]10 pg/mL) and not significantly increased in this system. ConclusionsMNP-021 coordinates transcriptomic restraint, transporter-level glucose handling, mitochondrial resilience, and pro-survival/pro-resolving signaling across neuron-microglia compartments, supporting TRPA1-tuned small-molecule modulation as a candidate strategy against dicarbonyl-linked neuro-metabolic stress.

physiology↗

bioRxiv2024

N-acylethanolamine acid amidase inhibition reduces SARS-CoV-2 infection in Human Precision cut-lung slices and downregulates NF-kappaB signalling.

Like other positive-sense RNA viruses, SARS-CoV-2 manipulates host lipid metabolism to facilitate its replication by enhancing lipogenesis and lipid droplet formation. In doing so, SARS-CoV-2 infection perturbs bioactive lipid levels associated with the inflammatory response. One of these, Palmitoylethanolamide (PEA) is suppressed during SARS-CoV-2 infection since it activates the Peroxisome Proliferator-Activated Receptor- (PPAR-), a transcription factor that suppresses the nuclear factor-B (NF-{kappa}B), which is mandatory to sustain SARS-CoV-2 replication. PEA levels are regulated by N-acylethanolamine acid amidase (NAAA), a lysosomal enzyme responsible for catalysing the breakdown of PEA. We hypothesized that NAAA inhibition might interfere with SARS-CoV-2 replication since it will lead PEA to accumulate, activating PPAR- and, consequently, suppressing NF-{kappa}B. Our results reveal that genetic or chemical ablation of NAAA significantly suppresses SARS-CoV-2 replication by three log10 in human-derived precision-cut lung slices. Therefore, we investigated whether inhibiting NAAA could influence NF-{kappa}B activation through the activation of PPAR-. We observed PPAR- increased expression in NAAA-/-cells, while PPAR- expression remained low in infected parental cells. As expected, the elevated PPAR- expression correlated with a parallel reduction in NF-{kappa}B activation when NAAA is ablated. These findings underscore NAAA as an essential host factor for SARS-CoV-2 replication and propose a potential mechanism of action rooted in the attenuation of NF-{kappa}B activation during viral replication. Author summaryOver the past three years, COVID-19 has claimed nearly 7 million lives worldwide, prompting extensive efforts to find effective treatments. While RNA-based vaccines have been developed rapidly, they alone have not completely halted the spread of the virus, making the search for antiviral therapies crucial. One promising approach targets the anti-inflammatory lipid PEA, which has shown some success in COVID-19 clinical trials. PEA is quickly degraded by the enzyme NAAA. Researchers have found that inhibiting NAAA can enhance and prolong PEA anti-inflammatory effects. NAAA inhibitors have already shown effectiveness in reducing chronic pain and lung inflammation in animal models and have also been effective against Zika virus replication. Our research focused on testing the NAAA inhibitor ARN726 against SARS-CoV-2. In human lung cells and lung tissue samples, ARN726 significantly reduced SARS-CoV-2 replication and inflammation. We discovered that this inhibition suppresses the NF-{kappa}B pathway, which the virus uses to fuel its replication and sustain Cytokine storm. Overall, our findings suggest that NAAA inhibitors like ARN726 could be repurposed to combat COVID-19 and potentially other coronaviruses, offering a novel and effective antiviral strategy.

microbiology↗