Biology subjects

Giachino, C.

Publications and source records attributed to Giachino, C..

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

Mapping the niche of breast cancer metastases in lung and liver

Breast cancer progression to visceral organs such as lung and liver is regarded as a dreadful event, unequivocally associated with a poor prognosis. Yet, these vital sites are characterized by highly diverse cellular microenvironments and physiological functions, suggesting that they may influence cancer cells behavior in divergent ways. Unexpectedly, we find that while the liver microenvironment fosters metastasis-promoting properties and boosts secondary spread, the lungs impose a roadblock to the same processes. Using patient data and tissues from rapid autopsy, as well as mouse models with barcode-mediated metastasis tracing, niche labeling technology and single cell analysis of both tumor cells and their direct microenvironment, we dissect cellular and molecular microenvironmental factors that impose this differential behavior. Among these, we identify BMP2-producing endothelial cells as critical players within the liver metastatic niche, capable to enhance metastasis-to-metastasis dissemination. Targeting BMP2 receptor on breast cancer cells suppresses their metastasis-forming ability. Altogether, we reveal a contrast in the site-specific behavior of lung and liver metastases in breast cancer, highlighting microenvironmental factors that contribute to this diversity, as well as organ-specific opportunities for intervention.

cancer biology↗

bioRxiv2022

LRRK2-G2019S SYNERGIZES WITH AGEING AND LOW-GRADE INFLAMMATION TO PROMOTE GUT AND PERIPHERAL IMMUNE CELL ACTIVATION THAT PRECEDE NIGROSTRIATAL DEGENERATION

BackgroundMutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinsons disease (PD). The incomplete penetrance of LRRK2 mutations suggest that additional hits are required for disease onset. We hypothesized that chronic low-grade inflammation interacts with LRRK2 G2019S, the most frequent PD-associated mutation, to activate peripheral and central immune reactions and drive age-dependent neurodegeneration. Methods and ResultsWe exposed wild-type and LRRK2 G2019S mice to a low chronic dose of lipopolysaccharide, and we performed a longitudinal analysis of central and peripheral immune reactions and neurodegeneration. Low-dose inflammation triggered nigrostriatal degeneration, macrophage/monocyte brain infiltration, and astro-/microgliosis. LRRK2 G2019S mice showed an early dysregulation of peripheral cytokines, increased CD4+ T-cell infiltration and -synuclein aggregation in the colon. Interestingly, peripheral immune activation and colonic -synuclein aggregation precede astro-/microgliosis and neurodegeneration. ConclusionsOur study suggests an early role of the peripheral immune system and the gut in LRRK2 PD and provides a novel model to study early therapeutic immune targets and biomarkers.

neuroscience↗

bioRxiv2018

Notch2 signaling regulates Id4 and cell cycle genes to maintain neural stem cell quiescence in the adult hippocampus

Neural stem cells (NSCs) in the adult hippocampal dentate gyrus (DG) can be quiescent or proliferative, but how they are maintained is largely unknown. With age DG NSCs become increasingly dormant, which impinges on neuron generation. We addressed how NSC activity is controlled and found that Notch2 promotes quiescence by regulating their transition to the activated state. Notch2-ablation induces cell cycle genes and markers of active NSCs. Conversely, quiescent NSC-associated genes, including Id4, are down regulated after Notch2 deletion. We found that Notch2 binds the Id4 promoter and positively regulates transcription. Similar to Notch2, Id4 overexpression promotes DG NSC quiescence and Id4 knockdown rescues proliferation, even when Notch2 signaling is activated. We show that Notch2 regulates age-dependent DG NSC dormancy and Notch2 inhibition rejuvenates neurogenesis in the DG of aged mice. Our data indicate that a Notch2-Id4 axis promotes adult DG NSC quiescence and dormancy.

neuroscience↗