Biology subjects

Palese, F.

Publications and source records attributed to Palese, F..

4 recordsLinked to original sources

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↗

bioRxiv2024

Proteostasis dysregulation in p.A53T-α-Synuclein iPSC-derived astrocytes exacerbates neurodegeneration in a Parkinson's disease model with Lewy-like pathology

Alpha-Synuclein (Syn) plays a central role in Parkinsons disease (PD) and the p.A53T mutation causes an early-onset familial form of PD with severe manifestations. The pathological effects of the p.A53T-Syn mutation have been extensively investigated in neurons, yet the consequences on astrocytes and astrocytic contribution to PD pathology are understudied. Here, we differentiated induced pluripotent stem cells from PD patients carrying the p.A53T-Syn mutation to astrocytes, which uncovered cell-intrinsic phenotypes, including calcium dyshomeostasis and accumulation of protein aggregates. Proteomic profiling and functional analyses revealed perturbed protein catabolic processes, involving the proteasome and autophagy, associated with lysosomal malfunction. Dopamine neurons co-cultured with p.A53T-Syn astrocytes displayed exacerbated neurodegeneration with hallmark Lewy-like pathologies, reversed by control astrocytes at least due to their ability to resolve neuronal Syn aggregates by endocytic clearance. Our findings underscore a critical impact of p.A53T-Syn on astrocytic protein quality control mechanisms, positioning astrocytes as important contributors to PD neuropathology. HighlightsO_LIiPSC-derived astrocytes from PD patients with the p.A53T-Syn mutation display cell-autonomous pathological phenotypes and toxic Syn accumulation C_LIO_LIProteome and functional analyses reveal failure of major proteostasis mechanisms in p.A53T-Syn astrocytes, largely related to lysosomal malfunction C_LIO_LIInherent Lewy-like pathological features are identified in p.A53T-Syn astrocyte-neuron co-cultures C_LIO_LIp.A53T-Syn astrocytes induce PD-relevant neuropathology to healthy neurons C_LIO_LIControl but not p.A53T-Syn astrocytes alleviate neuropathology in co-cultured neurons C_LI

neuroscience↗

bioRxiv2022

ADOLESCENT EXPOSURE TO LOW-DOSE THC DISRUPTS ENERGY BALANCE AND ADIPOSE ORGAN HOMEOSTASIS IN ADULTHOOD

One of cannabis most iconic effects is the stimulation of hedonic high-calorie eating - the munchies - yet habitual cannabis users are on average leaner than non-users. We asked whether this unexpected phenotype might result from lasting changes in energy balance established during adolescence, when habitual use of the drug often begins. We found that daily low-dose administration of cannabis intoxicating constituent, {Delta}9-tetrahydrocannabinol (THC), to adolescent mice causes an adult metabolic phenotype characterized by reduced fat mass, increased lean mass and utilization of fat as fuel, partial resistance to diet-induced obesity and dyslipidemia, and enhanced thermogenesis. Multi-omics analyses revealed that this phenotype is associated with multiple molecular anomalies in the adipose organ, which include ectopic overexpression of muscle-associated proteins and heightened anabolic processing. Thus, adolescent exposure to THC may promote an enduring pseudo-lean state that superficially resembles healthy leanness but might in fact be rooted in adipose organ dysfunction.

pharmacology and toxicology↗

bioRxiv2022

Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of Parkinson's disease

The lysosomal cysteine hydrolase N-acylethanolamine acid amidase (NAAA) deactivates the lipidderived mediator palmitoylethanolamide (PEA), an endogenous PPAR- agonist that is critically involved in the control of inflammation and nociception. In this study, we asked whether NAAA-regulated PEA signaling might contribute to the pathogenesis of Parkinsons disease (PD), a neurodegenerative disorder characterized by progressive loss of nigrostriatal dopamine neurons. Analyses of postmortem brain cortex and premortem blood-derived exosomes found elevated levels of NAAA expression in persons with PD compared to age-matched controls. Furthermore, in vitro experiments showed that the dopaminergic neurotoxins, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), enhanced NAAA expression and lowered PEA content in human SH-SY5Y cells. A similar effect was observed in dopamine neurons and, subsequently, in microglia following 6-OHDA injection in mice. Importantly, deletion of the Naaa gene or pharmacological inhibition of NAAA activity markedly attenuated both dopamine neuron death and parkinsonian symptoms in mice treated with 6-OHDA or MPTP. The results identify NAAA-regulated PEA signaling as a control node for dopaminergic neuron survival and a potential target for therapeutic intervention in PD.

pharmacology and toxicology↗