Biology subjects

Bossu, P.

Publications and source records attributed to Bossu, P..

4 recordsLinked to original sources

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↗

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↗

bioRxiv2018

Gene-Based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes For Alzheimer’s Disease

A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimers Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates.\n\nThree novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423. The ZNF423 gene resides in an Alzheimers disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.

genetics↗

bioRxiv2018

Elevated plasma ceramide levels in post-menopausal women

Circulating ceramide levels are abnormally elevated in age-dependent pathologies such as cardiovascular diseases, obesity and Alzheimers disease. Nevertheless, the potential impact of age on plasma ceramide levels has not yet been systematically examined. In the present study, we quantified a focused panel of plasma ceramides and dihydroceramides in a cohort of 164 subjects (84 women) 19 to 80 years of age. After adjusting for potential confounders, multivariable linear regression analysis revealed a positive association between age and ceramide (d18:1/24:0) ({beta} (SE) = 5.67 (2.38); p = .0198) and ceramide (d18:1/24:1) ({beta} (SE) = 2.88 (.61); p < .001) in women, and between age and ceramide (d18:1/24:1) in men ({beta} (SE) = 1.86 (.77); p = .0179). In women of all ages, but not men, plasma ceramide (d18:1/24:1) was negatively correlated with plasma estradiol (r = -0.294; p = .007). Finally, in vitro experiments in human cancer cells expressing estrogen receptors showed that incubation with estradiol (10 nM, 24 h) significantly decreased ceramide accumulation. Together, the results suggest that aging is associated with an increase in circulating ceramide levels, which in post-menopausal women may be at least partially dependent on lower estradiol levels.

biochemistry↗