Biology subjects

Dawson, V.

Publications and source records attributed to Dawson, V..

3 recordsLinked to original sources

bioRxiv2025

Dissecting the molecular landscape of Parkinson's disease and Parkinson's disease dementia using highly efficient snRNA-seq (HIF-snRNA-seq)

This study presents a transcriptomic analysis of the cingulate cortex (CING) in Parkinsons disease (PD) and Parkinsons disease dementia (PDD) using a High-efficiency single-nucleus RNA sequencing (HiF-snRNA-seq) protocol optimized for post-mortem brain samples. RNA quality prediction, poly-A tailing, and dCas9-targeted depletion enabled analysis of 77 high-quality samples from 240 cases, yielding over 2 million nuclei classified into seven major cell types. Disease conditions revealed altered astrocyte and microglia proportions, implicating their roles in neuroinflammation. Differential expression analysis identified unique and shared genes across PD and PDD, linked to synaptic remodeling, stress responses, and inflammation. Stage-specific analysis uncovered tau-dependent early-stage genes and inflammation-associated late-stage genes. This study highlights the CINGs central role in PD and PDD pathophysiology, offering insights into disease mechanisms and identifying candidate genes and pathways for therapeutic and biomarker development.

genomics↗

bioRxiv2021

Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic alpha-synuclein

Pathologic -synuclein (-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid {beta} precursor-like protein 1 (Aplp1) forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic -syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by -syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of -syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by -syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for -syn PFF induced pathology advances our understanding of the molecular mechanism of cell-to-cell transmission of pathologic -syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinsons disease and related -synucleinopathies. One Sentence SummaryAplp1 forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic -synuclein. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/442157v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1d746bforg.highwire.dtl.DTLVardef@65acb2org.highwire.dtl.DTLVardef@12cf2f0org.highwire.dtl.DTLVardef@19d6e_HPS_FORMAT_FIGEXP M_FIG Aplp1 and the Aplp1-Lag3 complex facilitates transmission of pathologic -synuclein. Aplp1 is a receptor that drives pathologic -syn transmission, and genetic depletion of Aplp1 can significantly reduce the -synuclein pathogenesis. Aplp1 and Lag3 forms an Aplp1-Lag3 complex that accounts for substantial binding of pathologic -syn to cortical neurons. Together Aplp1 and Lag3 play a major role in pathologic -syn internalization, transmission and toxicity. Double knockout of Aplp1 and Lag3 and or a Lag3 antibody that disrupts the Aplp1 and Lag3 complex almost completely blocks -syn PFF-induced neurodegeneration. C_FIG

neuroscience↗

bioRxiv2019

Functional dissection of Alzheimer’s disease brain gene expression signatures in humans and mouse models

Human brain transcriptomes can highlight biological pathways associated with Alzheimers disease (AD); however, challenges remain to link expression changes with causal triggers. We have examined 30 AD-associated, gene coexpression modules from human brains for overlap with 251 differentially-expressed gene sets from mouse brain RNA-sequencing experiments, including from models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus neurofibrillary tangle pathology and further reveal age- and sex-dependent expression signatures for AD progression. Human coexpression modules enriched for neuronal and/or microglial genes overlap broadly with signatures from mouse models of AD, Huntingtons disease, Amyotrophic Lateral Sclerosis, and also aging. Several human AD coexpression modules, including those implicated in the unfolded protein response and oxidative phosphorylation, were not activated in AD models, but instead were detected following other, unexpected mouse genetic manipulations. Our results comprise a powerful, cross-species resource and pinpoint experimental models for diverse features of AD pathophysiology from human brain transcriptomes.

systems biology↗