Biology subjects

Mallet, D.

Publications and source records attributed to Mallet, D..

3 recordsLinked to original sources

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

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use

The neurobiological mechanisms underlying compulsive alcohol use, a cardinal feature of alcohol use disorder, remain elusive. The key modulator of motivational processes dopamine (DA) is suspected to play an important role in this pathology, but its exact implication remains to be determined. Here, we found that rats expressing compulsive alcohol-related behavior, operationalized as punishment-resistant self-administration, showed a decrease in DA levels restricted to the dorsolateral territories of the striatum, the main output structure of the nigrostriatal DA pathway. We then causally demonstrated that a chemogenetic-induced selective hypodopaminergia of this pathway results in compulsive alcohol self-administration in rats otherwise resilient, accompanied by the emergence of alcohol withdrawal-like motivational impairments. These results demonstrate a major implication of tonic nigrostriatal hypodopaminergic state in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use.

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↗