Biology subjects

Katsel, P.

Publications and source records attributed to Katsel, P..

4 recordsLinked to original sources

bioRxiv2022

Brain Atlas for Glycoprotein Hormone Receptors at Single-Transcript Level

There is increasing evidence that anterior pituitary hormones, traditionally thought to have unitary functions in regulating single endocrine targets, act on multiple somatic tissues, such as bone, fat, and liver. There is also emerging evidence for anterior pituitary hormone action on brain receptors in mediating central neural and peripheral somatic functions. Here, we have created the most comprehensive neuroanatomical atlas on the expression of TSHRs, LHCGRs and FSHRs. We have used RNAscope, a technology that allows the detection of mRNA at single-transcript level, together with protein level validation, to document Tshr expression in 173 and Fshr expression in 353 brain regions, nuclei and sub-nuclei identified using the Atlas for the Mouse Brain in Stereotaxic Coordinates. We also identified Lhcgr transcripts in 401 brain regions, nuclei and sub-nuclei. Complementarily, we used ViewRNA, another single-transcript detection technology, to establish the expression of FSHRs in human brain samples, where transcripts were co-localized in MALAT1-positive neurons. In addition, we show high expression for all three receptors in the ventricular region--with yet unknown functions. Intriguingly, Tshr and Fshr expression in the ependymal layer of the third ventricle was similar to that of the thyroid follicular cells and testicular Sertoli cells, respectively. TSHRs were expressed specifically in tanycytes. In contrast, Fshrs were localized to NeuN-positive neurons in the granular layer of the dentate gyrus in murine and human brain--both are Alzheimers disease vulnerable regions. Our atlas thus provides a vital resource for scientists to explore the link between the stimulation or inactivation of brain glycoprotein hormone receptors on somatic function. New actionable pathways for human disease may be unmasked through further studies.

neuroscience↗

bioRxiv2019

Comprehensive post mortem brain samples analysis detects global reduction of multiple proteasome subunits expression in schizophrenia

OBJECTIVEA main challenge in the study of schizophrenia is its high heterogeneity. While it is generally accepted that there exist several biological mechanisms that may define distinct schizophrenia subtypes, they havent been identified yet. We applied comprehensive gene expression analysis, searching for molecular signals that differentiate patients with schizophrenia from healthy controls, and examined whether the identified signal characterizes a particular subgroup of the patients. METHODSWe performed transcriptome sequencing of 14 superior temporal gyrus (STG) samples of relatively young (mean age: 44) subjects with schizophrenia and 15 matched controls from the Stanley Medical Research Institute. Analyses of differential expression and pathway enrichment were applied and the results were compared with those obtained from an independent cohort of elderly (mean age: 74) patients. Replicability was then tested on six additional independent datasets of various brain regions. RESULTSThe two STG cohorts of relatively young and elderly subjects showed high replicability. Pathway enrichment analysis of the down-regulated genes pointed to proteasome-related pathways. Meta-analysis of differential expression identified down-regulation of 12 of 39 proteasome subunits in schizophrenia. Down-regulation of multiple proteasome subunits was replicated in six additional datasets (overall 8 cohorts, with 267 schizophrenia and 266 control samples, from 5 brain regions, were studied). This signal was concentrated in a subgroup of the patients. CONCLUSIONSWe detect global down-regulation of proteasome subunits in a subgroup of the patients with schizophrenia. The proteasome is a major intracellular protein degradation system, where ubiquitinated proteins (proteins bound by the small protein called ubiquitin) are targeted for degradation. We hypothesize that the down-regulation we detect leads to proteasome dysfunction that causes accumulation of ubiquitinated proteins. Such accumulation has recently been identified, also in a subgroup of the studied patients with schizophrenia. Thus, down-regulation of proteasome subunits might define a biological subtype of schizophrenia.

neuroscience↗

bioRxiv2018

Multiscale causal network models of Alzheimer’s disease identify VGF as a key regulator of disease

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimers disease (AD) remains elusive. To elucidate its complex nature, we constructed multiscale causal network models on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene and protein expression into probabilistic causal models that enabled detection and prioritization of high-confidence key drivers of AD, including the top predicted key driver VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was achieved, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF versus controls. Our findings support a causal and/or protective role for VGF in AD pathogenesis and progression.\n\nOne sentence summaryVGF protects against Alzheimers disease

genomics↗

bioRxiv2018

Connectivity analyses of bioenergetic changes in schizophrenia: Identification of novel treatments

We utilized a cell-level approach to examine glycolytic pathways in the DLPFC of subjects with schizophrenia (n=16) and control (n=16) subjects and found decreased mRNA expression of glycolytic enzymes in pyramidal neurons, but not astrocytes. To replicate these novel bioenergetic findings, we probed independent datasets for bioenergetic targets and found similar abnormalities. Next, we used a novel strategy to build a schizophrenia bioenergetic profile by a tailored application of the Library of Integrated Network-Based Cellular Signatures data portal (iLINCS) and investigated connected cellular pathways, kinases, and transcription factors using Enrichr. Finally, with the goal of identifying drugs capable of \"reversing\" the bioenergetic schizophrenia signature, we performed a connectivity analysis with iLINCS and identified peroxisome proliferator-activated receptor (PPAR) agonists as promising therapeutic targets. We administered a PPAR agonist to the GluN1 knockdown model of schizophrenia and found it improved long-term memory. Taken together, our findings suggest that tailored bioinformatics approaches, coupled with the LINCS library of transcriptional signatures of chemical and genetic perturbagens may be employed to identify novel treatment strategies for schizophrenia and related diseases.

neuroscience↗