Biology subjects

Labrie, V.

Publications and source records attributed to Labrie, V..

6 recordsLinked to original sources

bioRxiv2023

Human Endogenous Retrovirus Expression is Dynamically Regulated in Parkinson's Disease

Parkinsons disease (PD) is a progressive, debilitating neurodegenerative disease that afflicts approximately every 1000th individual. Recently, activation of genomic transposable elements (TE) has been suggested as a potential driver of PD onset. However, it is unclear where, when, and to what extent TEs are dysregulated in PD. Here, we performed a multi-tissue transcriptional analysis of multiple patient cohorts and identified TE transcriptional activation as a hallmark of PD. We find that PD patients exhibit up-regulation primarily of human endogenous retrovirus (HERV) transcripts in prefrontal cortex tissue, prefrontal neurons as well as in blood, and we demonstrate that TE activation in the blood is highest at the time of PD diagnosis. Supporting a potentially causal association between ERV dysregulation and PD heterogeneity, reduced gene dosage of the TE repressor Trim28 triggers transcriptional changes highly correlated to those measured in animal models of synucleinopathy (PFF-injection), and importantly, to those exhibited by patients themselves. These data identify ERV up-regulation as a common feature of central and peripheral PD etiology, and highlight potential roles for Trim28-dependent TEs in stratifying and monitoring PD and treatment compliance.

neuroscience↗

bioRxiv2020

Gut microbiome dysbiosis is associated with elevated toxic bile acids in Parkinson's disease

The gut microbiome can impact brain health and is altered in Parkinsons disease (PD) patients. Here, we investigate changes in the functional microbiome in the appendix of PD patients relative to controls by metatranscriptomic analysis. We find microbial dysbiosis affecting lipid metabolism, particularly an upregulation of bacteria responsible for secondary bile acid synthesis. Proteomic and transcript analysis corroborates a disruption in cholesterol homeostasis and lipid catabolism. Bile acid analysis reveals an increase in microbially-derived, toxic secondary bile acids. Synucleinopathy in mice induces similar microbiome alterations to those of PD patients. The mouse model of synucleinopathy has elevated DCA and LCA. An analysis of blood markers shows evidence of biliary abnormalities early in PD, including elevated alkaline phosphatase and bilirubin. Increased bilirubin levels are also evident before PD diagnosis. In sum, microbially-derived toxic bile acids are heightened in PD and biliary changes may even precede the onset of overt motor symptoms.

neuroscience↗

bioRxiv2019

Epigenetic contributions to hemisphere asymmetry in healthy brain, aging, and Parkinson’s disease

Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinsons disease (PD), but its molecular determinants are unknown. Here, we determine epigenetic differences involved in hemispheric asymmetry in the healthy and the PD brain. Neurons of the healthy brain exhibit numerous hemispheric differences in DNA methylation, which affect genes implicated in neurodegenerative diseases. In PD patients, hemispheric asymmetry in DNA methylation is even greater and involves many PD risk genes. The lateralization of clinical PD symptoms involves epigenetic, transcriptional, and proteomic differences across hemispheres that affect neurodevelopment, immune activation, and synaptic transmission. During aging, healthy neurons show a progressive loss of hemispheric asymmetry in the epigenome, which is amplified in PD. For PD patients, a long disease course is associated with greater hemispheric asymmetry in neuronal epigenomes than a short disease course. Hemispheric differences in epigenetic gene regulation are prevalent in neurons and may affect the progression and symptoms of PD.

neuroscience↗

bioRxiv2019

Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective

PD pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively profile DNA methylation at enhancers, genome-wide, in neurons of 57 PD patients and 48 control individuals. We found a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. Epigenetic dysregulation of enhancers in PD converge on transcriptional abnormalities affecting neuronal signaling and immune activation pathways. In particular, PD patients exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 inactivation in a neuronal cell line results in cytosine modification changes that are reciprocal to those observed in PD neurons. Furthermore, Tet2 inactivation in mice fully prevents dopaminergic neuronal loss in the substantia nigra induced by prior inflammation. Tet2 loss in mice also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a novel therapeutic target for PD.

neuroscience↗

bioRxiv2019

Genetics and Pathway Analysis of Normative Cognitive Variation in the Philadelphia Neurodevelopmental Cohort

An open challenge in human genetics is to better understand the link between genotype variation and the various molecular, cellular, anatomical and physiological systems that it can affect. To address this challenge, we performed genotype-phenotype-systems analysis for accuracy in nine cognitive tasks from the Philadelphia Neurodevelopmental Cohort (3,319 individuals aged 8-21 years). We report a region of genome-wide significance within the 3 end of the FBLN1 gene (p=4.6x10-8), associated with nonverbal reasoning, a heritable form of complex reasoning ability. Integration of published brain-specific omic maps reveals that FBLN1 shows greatest expression in the fetal brain, is a marker of neural progenitor cells, is differentially expressed in schizophrenia and increases genetic risk for bipolar disorder. These findings suggest that nonverbal reasoning and FBLN1 variation warrant further investigation in studies of neurodevelopmental disorders and psychosis. Using genotype-pathway analysis, we identify pathways related to development and to autonomic nervous system dysfunction associated with working memory accuracy. Top-ranking pathway genes include those genetically associated with multiple diseases with working memory deficits, such as schizophrenia and Parkinsons disease, and that are also markers for specific brain cell types. Our findings identify novel molecular players involved in specific cognitive tasks and link variants to genes, pathways, cell types, diseases and drugs. This work advances the "molecules-to-behaviour" view of cognition, and provides a framework for using systems-level organization of data for other biomedical domains.

genomics↗

bioRxiv2018

Differential DNA modification of an enhancer at the IGF2 locus affects dopamine synthesis in patients with major psychosis

Dopamine dysregulation is central to the pathogenesis of diseases with major psychosis, but its molecular origins are unclear. In an epigenome-wide investigation in neurons, individuals with schizophrenia and bipolar disorder showed reduced DNA modifications at an enhancer in IGF2, which disrupted the regulation of the dopamine synthesis enzyme tyrosine hydroxylase and striatal dopamine levels in transgenic mice. Epigenetic control of this enhancer may be an important molecular determinant of psychosis.

neuroscience↗