Biology subjects

Desaubry, L.

Publications and source records attributed to Desaubry, L..

6 recordsLinked to original sources

bioRxiv2025

Prokineticin-2 Upregulates GDNF in Astrocytes and Pharmacological Modulation of PK2 Receptors offers Neuroprotection in Experimental Models of Parkinson's Disease

Despite a wealth of preclinical studies establishing neuroprotective and neurorestorative properties of glial cell-line-derived neurotrophic factor (GDNF) in animal models of Parkinsons disease (PD), clinical trials utilizing direct intracranial infusion of GDNF protein, or adeno-associated virus (AAV)-mediated GDNF gene transfer has not achieved the desired efficacy, largely due to challenges in delivery methods. Given GDNFs strong potential for neuroprotection, alternative strategies to elevate its expression by beyond invasive injection or genetic manipulation remain a promising therapeutic avenue for PD. We previously reported that prokineticin signaling provides a compensatory protective response against dopaminergic neuronal degeneration in cell and animal models of PD. Herein, we report a novel finding that PK2 regulates GDNF gene expression in astrocytes, suggesting that PK2 signaling can be harnessed for neuroprotection in PD. Treatment of cultured astrocytes with the PK2 protein, PK2 gene overexpression or prokineticin receptor 1 (PKR1) agonist IS20 significantly induced the GDNF gene expression and the protein secretion, resulting in enhanced dopaminergic cell survival in cell culture models of PD. Importantly, systemic administration of IS20 through intraperitoneal or intranasal routes elevated GDNF levels in the mouse brain, including the nigrostriatal system. Furthermore, IS20 treatment conferred significant neuroprotective effects in both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and MitoPark transgenic mouse models of PD. Collectively, our translational findings suggest that pharmacological modulation PK2 signaling may unlock the full clinical benefit of GDNF, offering a novel and non-invasive therapeutic strategy for Parkinsons disease.

pharmacology and toxicology↗

bioRxiv2025

Selective mRNA translation determines adaptative mutability of melanoma cells to anti-BRAF/MEK combination therapy

During their inevitable evolution towards acquired resistance to anti-cancer targeted therapies, cancer cells adopt distinct gene expression profiles that allow them to transiently adapt to and tolerate the treatment. Similar to bacterial cells that transiently tolerate antibiotics, cancer cells surviving therapy can increase their mutation rate, enhancing the likelihood of acquiring resistance-conferring mutations and evolving into resistant cells. This adaptive mutability has been linked to transcriptional reprogramming of DNA damage repair mechanisms and effective therapeutic strategies to target such mechanisms are currently lacking. Here we show that translational control mediates the adaptive mutability of melanoma drug-tolerant cells by regulating the translation of the error-prone non-homologous end joining (NHEJ) component 53BP1. The specific inhibition of 5UTR-driven 53BP1 mRNA translation was sufficient to impair NHEJ and mutability. We found that the eIF4A RNA helicase, a key component of the eIF4F translation complex, regulates 53BP1 mRNA translation. Consequently, targeting the eIF4A with two small molecule inhibitors significantly delays the acquisition of resistance to combination of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutant melanoma xenograft models and cell lines by reducing the mutability of drug-tolerant cells. Our results demonstrate that a standard-of-care therapy for melanoma, by engaging non-genetic adaptation driven at the translational level, contributes to the evolution of drug-tolerant melanoma cells toward acquired resistance.

cancer biology↗

bioRxiv2025

Distinct Response Patterns to PHB Modulators in B Cell Lymphoma Models

B cell malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B cell lymphoma (DLBCL), rely on dysregulated B cell receptor (BCR) signaling for survival and proliferation. Prohibitin 1 and 2 (PHB1, PHB2) are multifunctional proteins involved in mitochondrial function, IgM-type BCR signaling and other key oncogenic pathways, making them potential therapeutic targets in lymphomas. Here, we assessed the effects of five PHB-targeting small molecules - FL3, Mel6, Mel56, IN44, and Fluorizoline - on lymphoma cell lines as proof-of-concept study. PHB transcript and protein quantities were differentially affected and distinct patterns of antiproliferative effects and viability were observed. Across cell models, FL3, Mel56, and Mel6 displayed strongest effects. FL3 and Mel56 exerted strong cytotoxic effects, while Mel6 primarily slowed proliferation. IN44 showed modest but selective cytotoxic effects in an ABC-DLBCL model, while Fluorizoline selectively stopped proliferation of a Burkitt lymphoma model. Non-malignant stromal cells remained largely unaffected by Mel56, highlighting a potential therapeutic window of this inhibitor. Replacing the native IgM constant region by IgG in the MEC-1 CLL line using CRISPR-Cas9 resulted in a somewhat reduced, but not abrogated effect of Mel56 suggesting effects on additional pathways beyond the BCR. Together these data provide proof-of-concept evidence for PHB inhibition as a potential strategy to target B cell lymphomas.

cancer biology↗

bioRxiv2024

Development of capsaicin derivatives as prohibitin ligands to modulate the Aurora kinase A/PHB2 interaction in cancer cells

Aurora kinase A/AURKA is a serine/threonine kinase overexpressed in a variety of solid and hematological malignancies. In the last decades, clinical trials aiming to counteract the overexpression of AURKA turned out to be largely unsuccessful. Meanwhile, recent discoveries pointed to new functions of AURKA at the subcellular level, including at mitochondria. At this location, AURKA induces organelle clearance by mitophagy acting in complex with the mitophagy mediator LC3, and its inner mitochondrial membrane receptor PHB2. The natural polyphenol xanthohumol was shown to act as a PHB2 ligand, altering the interaction between AURKA and PHB2 and restoring mitochondrial functions in cancer cells. However, its chemical nature prevents its broader use as an anticancer agent. Using Forsters Resonance Energy Transfer/Fluorescence Lifetime Imaging Microscopy (FRET/FLIM) in live breast cancer cells, we here explore the effects of alternative PHB ligands in altering the proximity between AURKA and PHB2. Among the already-available compounds, we found that the pungent natural product capsaicin partially alters the AURKA/PHB2 protein-protein proximity. We then synthesized 16 novel capsaicin analogs to enhance the effects of capsaicin. We found that replacing the long hydrophobic acyl moiety with a butyryl one increases the AURKA/PHB2 interaction. Among the capsaicin derivatives carrying this modification, we uncover that compounds 12 and 13 enhance the AURKA/PHB2 proximity. Molecular docking approaches corroborate FRET/FLIM data, and we visualize compounds 12 and 13 in complex with AURKA, PHB2 and LC3. We show that compounds 12 and 13 stabilize the AURKA/PHB2 interaction, and that they can bind to the inhibitory pocket of PHB2 and to the AURKA active site. Finally, we report that compound 13 specifically inhibits AURKA-dependent mitophagy, while leaving the activation of AURKA unaltered at centrosomes. Together, our data demonstrate that compound 13 is a promising PHB ligand acting on the AURKA/PHB2 interaction. Thanks to its specificity toward the mitochondrial roles of AURKA, it may provide the basis for the development of new anticancer drugs targeting the mitochondrial functions of AURKA.

cell biology↗

bioRxiv2024

Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination

Schwann cells are critical for the proper development and function of the peripheral nervous system, where they form a mutually beneficial relationship with axons. Past studies have highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long-term myelin maintenance and axon health, they may also be present at the Schwann cell-axon interface during development. Here, we expand on this work, showing that drug-mediated modulation of prohibitins in vitro disrupts myelination and confirming that Schwann cell-specific ablation of prohibitin 2 (Phb2) in vivo results in early and severe defects in peripheral nerve development. Using a proteomic approach in vitro, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on the presence of axonal signals. Furthermore, we show in vivo that loss of Phb2 in mouse Schwann cells causes ineffective proliferation and dysregulation of transcription factors EGR2 (KROX20), POU3F1 (OCT6) and POU3F2 (BRN2) that are necessary for proper Schwann cell maturation. Schwann cell-specific deletion of Jun, a transcription factor associated with negative regulation of myelination, confers partial rescue of the development defect seen in mice lacking Schwann cell Phb2. This work develops our understanding of Schwann cell biology, revealing that Phb2 may directly or indirectly modulate the timely expression of transcription factors necessary for proper peripheral nervous system development, and proposing candidates that may play a role in PHB2-mediated integration of axon signals in the Schwann cell.

neuroscience↗

bioRxiv2022

BCL-xL antagonizes the deleterious effects of KRAS on mitochondrial scaffolding

In addition to its canonical role as a regulator of mitochondrial outer membrane permeabilization, BCL-xL exerts diverse non canonical functions contributing to cancer cell aggressiveness. In particular it regulates KRAS intracellular activation levels. We herein explored the mechanistic basis for this effect by a spatially restricted biotin-labelling proteomic approach designed to characterize proteins whose proximity to KRAS, used as a bait, is BCL-xL dependant. BCL-xL loss relocalizes KRAS to the vicinity of mitochondrial proteins. Proximal proteins include the mitochondrial scaffold prohibitin 2 (PHB2), which also interacts with BCL-xL and the downregulation of which prevents BCL-xL sensitive effects of KRAS induced contacts between mitochondria and endosomes, and mitochondrial mass decrease. These results argue that BCL-xL prevents a negative feedback regulation of KRAS canonical signaling by KRAS interference with mitochondrial quality control.

cell biology↗