Biology subjects

Charbonnier, C.

Publications and source records attributed to Charbonnier, C..

3 recordsLinked to original sources

bioRxiv2024

Neuronal downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease hallmarks

We developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Out of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased A{beta} levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a 10-fold increased AD risk. PLCG2 LoF carriers exhibit low mRNA/protein PLCG2/PLC{gamma}2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single nuclei RNAseq analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexin in neurons. In conclusion, PLC{gamma}2 downregulation could increase AD risk by impairing synaptic functions and increasing the A{beta} levels and Tau phosphorylation in neurons.

neuroscience↗

bioRxiv2021

Penetrance estimation of SORL1 loss-of-function variants using a family-based strategy adjusted on APOE genotypes suggest a non-monogenic inheritance

For complex disorders, estimating the age-related penetrance associated with rare variants of strong effect is essential before a putative use for genetic counseling or disease prevention. However, rarity and co-occurrence with other risk factors make such estimations difficult. In the context of Alzheimer disease, we present a survival model to estimate the penetrance of SORL1 rare (allele frequency< 1%) Loss-of-Function variants (LoF) while accounting for APOE-{varepsilon}4, the main risk factor (allele frequency[~] 14% in Caucasians). We developed an efficient strategy to compute penetrance estimates accounting for both common and rare genetic variants based on available penetrance curves associated with common risk factors and using incomplete pedigree data to quantify the additional risk conferred by rare variants. Our model combines: (i) a baseline for non-carriers of SORL1 LoF variants, stratified by APOE genotypes derived from the Rotterdam study and (ii) an age-dependent proportional hazard effect for SORL1 LoF variants estimated from pedigrees with a proband carrying such a variant. We embed this model into an Expectation-Maximisation algorithm to accommodate for missing genotypes. Confidence intervals were computed by bootstraps. To correct for ascertainment bias, proband phenotypes were omitted. We obtained penetrance curves associated with SORL1 LoF variants at the digenic level. By age 70, we estimate a 100% penetrance of SORL1 LoF variants only among APOE-{varepsilon}4{varepsilon}4 carriers, while penetrance is 56%[40% - 72%] among {varepsilon}4 heterozygous carriers and 37%[26% - 51%] among {varepsilon}4 non-carriers. We conclude that rare SORL1 LoF variants should not be used for genetic counseling regardless of the APOE status.

genetics↗

bioRxiv2020

Deuterated rhodamines for protein labelling in nanoscopy

Rhodamine molecules are setting benchmarks in fluorescence microscopy. Herein, we report the deuterium (d12) congeners of tetramethyl(silicon)rhodamine, obtained by isotopic labelling of the four methyl groups, which improves photophysical (i.e. brightness, lifetimes) and chemical (i.e. bleaching) properties. We explore this finding for SNAP- and Halo-tag labelling, and highlight enhanced properties in several applications, such as Forster resonance energy transfer, fluorescence activated cell sorting, fluorescence lifetime microscopy and stimulated emission depletion nanoscopy. We envision deuteration as a generalizable concept to improve existing and develop new Chemical Biology Probes.

physiology↗