Biology subjects

Fauvelle, F.

Publications and source records attributed to Fauvelle, F..

5 recordsLinked to original sources

bioRxiv2025

The metabolic kinase LKB1 shapes the enteric nervous system bymitigating the oxidative stress and p53 activity

The enteric nervous system (ENS) comprises ganglia of neurons and glial cells derived from migratory multipotent neural crest cells. While the molecular mechanisms of ENS development are well-studied, the involvement of metabolic processes has received less attention. We previously showed that the tumor suppressor kinase LKB1 is essential for the trophic maintenance of postnatal ENS. Here we examined LKB1s role in ENS formation using a genetically engineered mouse model that conditionally inactivates Lkb1 in neural crest progenitors during gut invasion. We conducted a comprehensive phenotyping of the ENS through histology and 3D imaging of cleared tissue, combining lightsheet microscopy with adaptive optics confocal microscopy. We found that Lkb1 loss impairs early neuronal differentiation, followed by glial degeneration, leading to hypoganglionosis and compromised digestive tissue integrity. Metabolite profiling of digestive tracts revealed an increase of oxidative stress upon Lkb1 ablation. In vitro, Lkb1 knockdown induced oxidative stress in neural crest progenitors and their glial derivatives, causing DNA damage and p53 activation. Ablation of p53 rescued glial specification under these conditions. In vivo, hyperphosphorylation of p53 was also observed; however, deletion of p53 alleles in Lkb1 mutants did not restore enteric neurons number. Instead, it improved axonal fiber organization and partially rescued digestive tissue integrity. These findings establish LKB1 as a key metabolic regulator on both the development and maintenance of the ENS, suggesting that aberrant LKB1 signaling may contribute to human enteric glioneuropathies. HighlightsO_LILKB1 loss in enteric progenitors results in extensive hypoganglionosis and disrupts gut tissue homeostasis. C_LIO_LIDuring embryogenesis, LKB1 shapes enteric ganglia by sequentially regulating neuronal differentiation and preserving glial cells, partly by limiting oxidative stress and p53 activity. C_LIO_LIThese findings establish LKB1 as a critical regulator of neural crest cell formation, highlighting its multifaceted roles and potential pathological implications in digestive neuropathies. C_LI

developmental biology↗

bioRxiv2025

Daily intermittent fasting is an effective multiscale treatment in preclinical models of absence epilepsy

Absence epilepsy (AE) is characterized by brief but frequent seizures with loss of consciousness. Existing treatments have heavy side effects, are only partially effective and do not address the comorbidities, including cognitive and social deficits. A tripartite link between seizures, cognitive deficits and diet has been established. We focused on intermittent fasting (IF), a regime where daily periods of fasting alternate with periods of food intake, with no restrictions in the type or quantity of food consumed. To date, the effects of IF on infantile epilepsy have not been addressed. We evaluated the therapeutic potential of a daily, one-month protocol of IF on three established mouse models of AE: the Grm7AAA KI mouse, the Scn2a haploinsufficiency mouse and the pharmacologically-induced AY-9944 mouse model. We show a reduction of the seizure frequency in all models, as well as an improvement of the sociability deficits observed in two of the models, with no adverse effects. Focusing on the Grm7AAA KI model, we performed RNA sequencing in a one of the key brain areas of the absence seizure circuit, the thalamus. We detected a deregulation of genes involved in vascularization associated with the development of malformed blood vessels in epileptic mice. Along with its anti-seizure effects, IF was able to counteract both abnormal gene expression and vessel morphology. This study demonstrates for the first time the positive effects of IF on AE and could facilitate the implementation of the diet in clinical trials.

neuroscience↗

bioRxiv2022

Re-routing metabolism by the mitochondrial pyruvate carrier inhibitor MSDC-0160 attenuates neurodegeneration in a rat model of Parkinson's disease

BackgroundA growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinsons disease (PD). Central regulators of energy production, mitochondria are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160. MethodsWe investigated behavioral, cellular and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrial related processes through the expression of pivotal mitochondrial enzymes in dorsal striatal biopsies and the level of metabolites in serum samples using nuclear magnetic resonance spectroscopy (NMR)-based metabolomics. ResultsMSDC-0160 treatment in unilateral 6-OHDA rats improved motor behavior, decreased dopaminergic denervation and reduced mTOR activity and neuroinflammation. Concomitantly, MSDC-0160 administration strongly modified energy metabolism as revealed by increased ketogenesis, beta oxidation and glutamate oxidation to satisfy energy needs and maintain energy homeostasis. ConclusionMSDC-0160 exerts its neuroprotective effect through reorganization of multiple pathways connected to energy metabolism.

neuroscience↗

bioRxiv2021

Early diagnosis of Parkinson's disease: A cross-species biomarker

BackgroundCare management of Parkinsons disease (PD) patients currently remains symptomatic, especially because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Detecting PD earlier therefore represents a key step for developing therapies able to delay or slow down its progression. MethodsWe investigated metabolic markers in three different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 2 cohorts of de novo PD patients (n = 95). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics. ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence, and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, non-motor signs and very interestingly, also discriminated PD patients from healthy subjects. ConclusionFrom our translational study which included three animal models and two PD patient cohorts, we propose a promising composite biomarker exhibiting a high level of predictivity for PD diagnosis in its early phase, before motor symptoms appearance. FundingsANR, DOPALCOMP, Institut National de la Sante et de la Recherche Medicale, Grenoble Alpes University.

pathology↗

bioRxiv2020

Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells via modulating metabolism and death pathways.

Rhabdomyosarcoma (RMS) is the most frequent form of pediatric soft-tissue sarcoma. It is divided into 2 main subtypes: ERMS (embryonal) and ARMS (alveolar). Current treatments are based on chemotherapy, surgery and radiotherapy. 5-year survival rate remains of 70% since 2000, despite several clinical trials. RMS cells are thought to derive from muscle lineage precursors. During development, myogenesis is characterized by primary expansion of myoblasts, elimination of those in excess by cell death and the differentiation of the remaining ones into myotubes and myofibers. The idea that these processes could be hijacked by tumor cells to sustain their oncogenic transformation has emerged, while RMS is being considered as the Mister Hydes side of myogenesis. Thus, focusing on myogenic developmental programs could help understanding RMS molecular aetiology. Following this idea, we decided to concentrate on ANT1, which is involved in myogenesis and is the underlying cause of genetic disorders associated with muscle degeneration. ANT1 is a mitochondrial protein, which has a functional duality, as it is involved both in metabolism via regulation of ATP/ADP release from mitochondria, but also in apoptosis as part as the mitochondria Permeability Transition Pore (mPTP). By bioinformatic analysis of transcriptomic datasets, we observed that ANT1 is expressed at low levels in RMS. Using CRISPR-Cas9 technology, we showed that decreased ANT1 expression confers selective advantages to RMS cells in terms of proliferation and resistance to stress-induced death. These effects result notably from a metabolic switch. Restoration of ANT1 expression using a Tet-On system is sufficient to prime tumor cells to death and to increase their sensitivity to chemotherapies. Thus, modulation of ANT1 activity could appear as an appealing therapeutic approach in RMS management.

cancer biology↗