Biology subjects

Coetzee, G. A.

Publications and source records attributed to Coetzee, G. A..

4 recordsLinked to original sources

bioRxiv2024

Gene expression asymmetry in Parkinson's Disease; variation of CCT and BEX gene expression levels are correlated with hemisphere specific severity

Parkinsons Disease (PD) develops unilaterally, which may be related to brain hemispheric differences in gene expression. Here we measured bulk RNA-seq levels in neuronal nuclei obtained from prefrontal cortex postmortem brain samples from males and females with PD and from healthy controls. Left and right hemispheres from each brain were related the side of symptom onset and compared. We employed two a priori approaches; first we identified genes differentially expressed between PD and controls and between left vs right PD brain hemispheres. Second, we examined the presence of, and correlates to, variable asymmetry seen in candidate PD differentially expressed genes. We found large variation among individuals with PD, and PD stratification by gene expression similarity was required for patterns of genetic asymmetry to emerge. For a subset of PD brains, hemispherical variation of CCT and BEX gene levels correlated with the side of PD symptom onset.

neuroscience↗

bioRxiv2021

GLOBAL EFFECTS OF A PD RISK-SNP AT THE ALPHA-SYNUCLEIN LOCUS

SUMMARYOne of the most significant Parkinsons disease (PD) risk variants, rs356182, is located at the PD-associated locus near the alpha-synuclein encoding gene, SNCA. SNCA-proximal variants, including rs356182, are thought to function in PD via allele-specific regulatory effects on SNCA expression. However, this interpretation discounts the complex activity of genetic enhancers and possible nonconical effects of alpha-synuclein. Here we investigate a novel risk mechanism for rs356182. We use CRISPR-Cas9 in LUHMES cells, a model for dopaminergic neurons, to generate precise hemizygous lesions at rs356182. The PD-protective (A/-), PD-risk (G/-), and WT (A/G) strains are differentiated into dopaminergic neurons then compared transcriptionally and morphologically. We observe effects not typically ascribed to SNCA; hundreds of differentially expressed genes associated with neuronal differentiation and axonogenesis. Together, the data implicate a risk mechanism for rs356182 in which the risk-allele (G) is associated with abnormal neuronal differentiation. We speculate the disease-relevant effect originates as a diminished population of DA neurons leading to the predisposition for PD later in life.

neuroscience↗

bioRxiv2020

Parkinsons Disease Genetic Risk Evaluation in Microglia Highlights Autophagy and Lysosomal Genes

Genome-wide association studies (GWAS) have uncovered thousands of single nucleotide polymorphisms (SNPs) that are associated with Parkinsons disease (PD) risk. The functions of most of these SNPs, including the cell type they influence, and how they affect PD etiology remain largely unknown. To identify functional SNPs, we aligned PD risk SNPs within active regulatory regions of DNA in microglia, a cell type implicated in PD development. Out of 6,749 SNPs of interest from the most recent PD GWAS metanalysis, 73 were located in open regulatory chromatin as determined by both ATAC-seq and H3K27ac ChIP-seq. We highlight a subset of SNPs that are favorable candidates for further mechanistic studies. These SNPs are located in regulatory DNA at the SLC50A1, SNCA, BAG3, FBXL19, SETD1A, and NUCKS1 loci. A network analysis of the genes with risk SNPs in their promoters, implicated substance transport, involving autophagy and lysosomal genes. Our study provides a more focused set of risk SNPs and their associated risk genes as candidates for further follow-up studies, which will help identify mechanisms in microglia that increase the risk for 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↗