Biology subjects

Polioudakis, D.

Publications and source records attributed to Polioudakis, D..

5 recordsLinked to original sources

bioRxiv2023

Disease-specific selective vulnerability and neuroimmune pathways in dementia revealed by single cellgenomics

Summary/AbstractThe development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNAseq and ATACseq in Alzheimer disease (AD), Frontotemporal degeneration (FTD), and Progressive Supranuclear Palsy (PSP), analyzing 40 participants, yielding over 1.4M cells from three brain regions ranging in vulnerability and pathological burden. We identify 35 shared disease-associated cell types and 14 that are disease-specific, replicating those previously identified in AD. Disease-specific cell states represent molecular features of disease-specific glial-immune mechanisms and neuronal vulnerability in each disorder, layer 4/5 intra-telencephalic neurons in AD, layer 2/3 intra-telencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We infer intrinsic disease-associated gene regulatory networks, which we empirically validate by chromatin footprinting. We find that causal genetic risk acts in specific neuronal and glial cells that differ across disorders, primarily non-neuronal cells in AD and specific neuronal subtypes in FTD and PSP. These data illustrate the heterogeneous spectrum of glial and neuronal composition and gene expression alterations in different dementias and identify new therapeutic targets by revealing shared and disease-specific cell states.

neuroscience↗

bioRxiv2019

Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders

Neurodevelopmental disorders are highly heritable and associated with spatially-selective disruptions of brain anatomy. The logic that translates genetic risks into spatially patterned brain vulnerabilities remains unclear but is a fundamental question in disease pathogenesis. Here, we approach this question by integrating (i) in vivo neuroimaging data from patient subgroups with known causal genomic copy number variations (CNVs), and (ii) bulk and single-cell gene expression data from healthy cortex. First, for each of six different CNV disorders, we show that spatial patterns of cortical anatomy change in youth are correlated with spatial patterns of expression for CNV region genes in bulk cortical tissue from typically-developing adults. Next, by transforming normative bulk-tissue cortical expression data into cell-type expression maps, we further link each disorders anatomical change map to specific cell classes and specific CNV-region genes that these cells express. Finally, we establish convergent validity of this "transcriptional vulnerability model" by inter-relating patient neuroimaging data with measures of altered gene expression in both brain and blood-derived patient tissue. Our work clarifies general biological principles that govern the mapping of genetic risks onto regional brain disruption in neurodevelopmental disorders. We present new methods that can harness these principles to screen for potential cellular and molecular determinants of disease from readily available patient neuroimaging data.

neuroscience↗

bioRxiv2018

Single-cell in situ transcriptomic map of astrocyte cortical layer diversity

During organogenesis, patterns and gradients of gene expression underlie organization and diversified cell specification to generate complex tissue architecture. While the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells are diversified to mimic neuronal laminae or show distinct layering. To determine the molecular architecture of the mammalian cortex, we developed a high content pipeline that can quantify single-cell gene expression in situ. The Large-area Spatial Transcriptomic (LaST) map confirmed expected cortical neuron layer organization and also revealed a novel neuronal identity signature. Screening 46 candidate genes for astrocyte diversity across the cortex, we identified grey matter superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from neurons. Astrocyte layers formed in early postnatal cortex and mostly persisted in adult mouse and human cortex. Mutations that shifted neuronal post-mitotic identity or organization were sufficient to alter glial layering, indicating an instructive role for neuronal cues. In normal mouse cortex, astrocyte layer patterns showed area diversity between functionally distinct cortical regions. These findings indicate that excitatory neurons and astrocytes cells are organized into distinct lineage-associated laminae, which give rise to higher order neuroglial complexity of cortical architecture.

neuroscience↗

bioRxiv2018

A single cell transcriptomic analysis of human neocortical development

Defining the number, proportion, or lineage of distinct cell types in the developing human brain is an important goal of modern brain research. We defined single cell transcriptomic profiles for 40,000 cells at mid-gestation to identify cell types in the developing human neocortex. We define expression profiles corresponding to all known major cell types at this developmental period and identify multiple transcription factors and co-factors expressed in specific cell types, providing an unprecedented resource for understanding human neocortical development including the first single-cell characterization of human subplate neurons. We characterize major developmental trajectories during early neurogenesis, showing that cell type differentiation occurs on a continuum that involves transitions that tie cell cycle progression with early cell fate decisions. We use these data to deconvolute regulatory networks and map neuropsychiatric disease genes to specific cell types, implicating dysregulation of specific cell types, as the mechanistic underpinnings of several neurodevelopmental disorders. Together these results provide an extensive catalog of cell types in human neocortex and extend our understanding of early cortical development, human brain evolution and the cellular basis of neuropsychiatric disease.\n\nOne Sentence SummaryComprehensive single cell transcriptomes in developing human cortex inform models of cell diversity, differentiation and disease risk.

neuroscience↗

bioRxiv2018

Whole genome sequencing in multiplex families reveals novel inherited and de novo genetic risk in autism

Genetic studies of autism spectrum disorder (ASD) have revealed a complex, heterogeneous architecture, in which the contribution of rare inherited variation remains relatively un-explored. We performed whole-genome sequencing (WGS) in 2,308 individuals from families containing multiple affected children, including analysis of single nucleotide variants (SNV) and structural variants (SV). We identified 16 new ASD-risk genes, including many supported by inherited variation, and provide statistical support for 69 genes in total, including previously implicated genes. These risk genes are enriched in pathways involving negative regulation of synaptic transmission and organelle organization. We identify a significant protein-protein interaction (PPI) network seeded by inherited, predicted damaging variants disrupting highly constrained genes, including members of the BAF complex and established ASD risk genes. Analysis of WGS also identified SVs effecting non-coding regulatory regions in developing human brain, implicating NR3C2 and a recurrent 2.5Kb deletion within the promoter of DLG2. These data lend support to studying multiplex families for identifying inherited risk for ASD. We provide these data through the Hartwell Autism Research and Technology Initiative (iHART), an open access cloud-computing repository for ASD genetics research.

genomics↗