Biology subjects

Raskind, W. H.

Publications and source records attributed to Raskind, W. H..

3 recordsLinked to original sources

bioRxiv2023

A data-fusion approach to identifying developmental dyslexia from multi-omics datasets

This exploratory study tested and validated the use of data fusion and machine learning techniques to probe high-throughput omics and clinical data with a goal of exploring the etiology of developmental dyslexia. Developmental dyslexia is the leading learning disability in school aged children affecting roughly 5-10% of the US population. The complex biological and neurological phenotype of this life altering disability complicates its diagnosis. Phenome, exome, and metabolome data was collected allowing us to fully explore this system from a behavioral, cellular, and molecular point of view. This study provides a proof of concept showing that data fusion and ensemble learning techniques can outperform traditional machine learning techniques when provided small and complex multi-omics and clinical datasets. Heterogenous stacking classifiers consisting of single-omic experts/models achieved an accuracy of 86%, F1 score of 0.89, and AUC value of 0.83. Ensemble methods also provided a ranked list of important features that suggests exome single nucleotide polymorphisms found in the thalamus and cerebellum could be potential biomarkers for developmental dyslexia and heavily influenced the classification of DD within our machine learning models.

bioinformatics↗

bioRxiv2020

Novel TREM2 splicing isoform that lacks the V-set immunoglobulin domain is abundant in the human brain

TREM2 is an immunoglobulin-like receptor expressed by certain myeloid cells, such as macrophages, dendritic cells, osteoclasts and microglia. In the brain, TREM2 plays an important role in the immune function of microglia, and its dysfunction is linked to various neurodegenerative conditions in humans. Ablation of TREM2 or its adaptor protein TYROBP causes Polycystic Lipo-Membranous Osteodysplasia with Sclerosing Leukoencephalopathy (also known as Nasu-Hakola disorder) with early onset of dementia, while some missense variants in TREM2 are associated with an increased risk of late-onset Alzheimers disease. Human TREM2 gene is a subject to alternative splicing, and its major, full-length canonical transcript encompasses 5 exons. Herein, we report a novel alternatively spliced TREM2 isoform without exon 2 ({Delta}e2), which constitutes a sizable fraction of TREM2 transcripts and has highly variable inter-individual expression in the human brain (average frequency 10%; range 3.7-35%). The protein encoded by {Delta}e2 lacks a V-set immunoglobulin domain from its extracellular part but retains its transmembrane and cytoplasmic domains. We demonstrated {Delta}e2 protein expression in TREM2-positive THP-1 cells, in which the expression of full-length transcript was precluded by CRISPR/Cas9 disruption of the exon 2 coding frame. In "add-back" experiments, overexpression of full-length, but not {Delta}e2 TREM2, restored phagocytic capacity and promoted interferon type I response in the knockout cells. Our findings suggest that expression of a {Delta}e2 splice isoform may modify the dosage of full-length transcript potentially weakening some TREM2 receptor functions in the human brain.

immunology↗

bioRxiv2018

TREM2 R47H exacerbates immune response in Alzheimer’s disease brain

The R47H variant in the microglial TREM2 receptor is a strong risk factor for Alzheimers disease (AD). To characterize processes affected by R47H we performed integrative network analysis of genes expressed in brains of AD patients with R47H, sporadic AD without the variant and patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), a systemic disease with early onset dementia caused by loss-of function mutations in TREM2 or its adaptor TYROBP. While sporadic AD had few perturbed microglial and immune genes, TREM2 R47H AD demonstrated upregulation of interferon type I response and pro-inflammatory cytokines accompanied by induction of NKG2D stress ligands. In contrast, PLOSL had distinct sets of highly perturbed immune and microglial genes that included inflammatory mediators, immune signaling, cell adhesion and phagocytosis. TREM2 knock-out in THP1, a human myeloid cell line that constitutively expresses the TREM2-TYROBP receptor, inhibited response to the viral RNA mimetic poly(I:C), and overexpression of ectopic TREM2 restored the response. Compared to wild type protein, R47H TREM2 had higher stimulatory effect on the interferon type I response signature. Our findings point to a role of the TREM2 receptor in the control of the interferon type I response in myeloid cells and provide insight regarding the contribution of R47H TREM2 to AD pathology.

genetics↗