Biology subjects

Audet, S.

Publications and source records attributed to Audet, S..

3 recordsLinked to original sources

bioRxiv2024

Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis

ABSTRACTLipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo. We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease. HIGHLIGHTSO_LILipid droplets (LD) normally form in neurons across species Neuronal LD are regulated by a conserved gene network C_LIO_LINeuronal LD regulation plays a conserved and sex-biased role in maintaining energy homeostasis C_LIO_LILD regulation supports ER and mitochondrial function in hunger-activated neurons C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/613929v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1936e92org.highwire.dtl.DTLVardef@40478aorg.highwire.dtl.DTLVardef@18d5faorg.highwire.dtl.DTLVardef@882ee9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Mapping the peripheral immune landscape of Parkinson's disease patients with single-cell sequencing

Parkinsons Disease (PD) is most recognized for its impact on the central nervous system. However, recent breakthroughs underscore the crucial role of interactions between central and peripheral systems in PDs pathogenesis. The spotlight is now shifting as we explore beyond the central nervous system, discovering that peripheral changes such as inflammatory dysfunctions may predict the rate of disease progression and severity. Despite more than 200 years of research on PD, reliable diagnostic or progression biomarkers and effective disease-modifying treatments are still lacking. Additionally, the cellular mechanisms that drive changes in immunity are largely unknown. Thus, understanding peripheral immune signatures could lead to earlier diagnosis and more effective treatments for PD. Here, we sought to define the transcriptomic alterations of the complete peripheral immune cell compartment by single-cell RNA- and T-cell receptor-sequencing with hopes of uncovering PD signatures and potential peripheral blood biomarkers. Following transcriptional profiling of 78 876 cells from 10 healthy controls and 14 PD donors, we observed five major classes of immune cell types; myeloid (monocytes, dendritic cells) and lymphoid (T, B, natural killer) cells from which we identified 38 cellular subtypes following bioinformatic re-clustering. Comparing immune cell subtypes and phenotypes between PD patients and healthy controls revealed notable features of PD: 1) a significant shift of classical CD14+ monocytes towards an activated CD14+/CD83+ state, 2) changes in lymphocyte subtype abundance, including a significant decrease in CD4+ naive and mucosal-associated invariant T-cells subtypes, along with an increase in CD56+ natural killer cells, 3) the identification by T-cell receptor sequencing of several PD specific T-cell clones shared between multiple patients, suggesting the implication of common epitopes in PD pathogenesis, 4) a notable increase in the expression of activation signature genes, including the AP-1 stress-response transcription factor complex, across all PD cell types. This signal was not present in atypical parkinsonism patients with multiple systems atrophy or progressive supranuclear palsy. Overall, we present a comprehensive atlas of peripheral blood mononuclear cells from control and PD patients which should serve as a tool to improve our understanding of the role the immune cell landscape plays in PD pathogenesis.

genetics↗

bioRxiv2024

RFC1 regulates the expansion of neural progenitors in the developing zebrafish cerebellum

DNA replication and repair are basic yet essential molecular processes for all cells. RFC1 encodes the largest subunit of the Replication Factor C (RFC), which is a clamp-loader during DNA replication and repair. Intronic repeat expansion in RFC1 has recently been associated with so-called RFC1-related disorders, which mainly encompass late-onset cerebellar ataxias. However, the mechanisms that make certain tissues more susceptible to defects in these universal pathways remain mysterious. In this study, we provide the first investigation of RFC1 gene function in vivo using zebrafish. We showed that RFC1 is expressed in neural progenitor cells within the developing cerebellum and that it is necessary to maintain these cells genomic integrity during neurogenic maturation. Accordingly, RFC1 loss-of-function leads to a severe cerebellar phenotype due to impaired neurogenesis of both Purkinje and granule cells. Our data thus point to a specific role of RFC1 in the developing cerebellum, paving the way for a better understanding of the pathogenic mechanisms underlying RFC1-related disorders.

developmental biology↗