Gene Expression Profiles in Parkinson Disease Prefrontal Cortex Implicate FOXO1 and Genes under Its Transcriptional Regulation

Parkinson disease (PD) is a complex neurodegenerative disorder with largely unknown genetic mechanisms. While the degeneration of dopaminergic neurons in PD mainly takes place in the substantia nigra pars compacta (SN) region, other brain areas, including the prefrontal cortex, develop Lewy bodies, the neuropathological hallmark of PD. We generated and analyzed expression data from the prefrontal cortex Brodmann Area 9 (BA9) of 27 PD and 26 control samples using the 44K One-Color Agilent 60-mer Whole Human Genome Microarray. All samples were male, without significant Alzheimer disease pathology and with extensive pathological annotation available. 507 of the 39,122 analyzed expression probes were different between PD and control samples at false discovery rate (FDR) of 5%. One of the genes with significantly increased expression in PD was the forkhead box O1 (FOXO1) transcription factor. Notably, genes carrying the FoxO1 binding site were significantly enriched in the FDR–significant group of genes (177 genes covered by 189 probes), suggesting a role for FoxO1 upstream of the observed expression changes. Single-nucleotide polymorphisms (SNPs) selected from a recent meta-analysis of PD genome-wide association studies (GWAS) were successfully genotyped in 50 out of the 53 microarray brains, allowing a targeted expression–SNP (eSNP) analysis for 52 SNPs associated with PD affection at genome-wide significance and the 189 probes from FoxO1 regulated genes. A significant association was observed between a SNP in the cyclin G associated kinase (GAK) gene and a probe in the spermine oxidase (SMOX) gene. Further examination of the FOXO1 region in a meta-analysis of six available GWAS showed two SNPs significantly associated with age at onset of PD. These results implicate FOXO1 as a PD–relevant gene and warrant further functional analyses of its transcriptional regulatory mechanisms

Structure and Dynamics of the Severe Acute Respiratory Syndrome Coronavirus 2 - Bound Angiotensin-Converting Enzyme 2 : Insight into the Role of a Conserved Disulfide

Color poster with text and images.Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a pathogenic coronavirus in humans. Coronaviruses are large RNA viruses which contain spike proteins on their surface, giving the appearance of a crown and the name coronavirus. These spike proteins, known as S-proteins, are glycoproteins and type-I transmembrane proteins. The spike contains a receptor-binding domain that functions by binding to the peptidase domain of the angiotensin-converting enzyme 2 (ACE2) receptor which is expressed in human lung, heart, kidney, and intestinal cells. For this reason, it is of critical significance to understand the structure of these proteins and the ACE2 host cell receptor they bind to as well as the mechanism of virus entry into the host cell. The binding and entry of the viral protein are impacted by the thiol-disulfide balance on the cell surface. In the present study, the disulfide linkage C480-C488, located close to the binding surface, has been probed by either converting them to thiols or by mutating both cysteines to alanine. The effect of these alterations on structure, key interactions, and protein motions were probed by using long-duration molecular dynamics simulations on a GPU-based high-performance computing cluster. The results of these simulations will be presented.Council on Undergraduate Research; National Institutes of Health; University of Wisconsin--Eau Claire Office of Research and Sponsored Program

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease.

International audienceStudying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-β peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Aβ metabolism or signalling, and for which animal or cellular models have already been developed