Biology subjects

Xu, E.

Publications and source records attributed to Xu, E..

29 records · Page 2Linked to original sources

bioRxiv2022

Amygdalar and ERC Rostral Atrophy and Tau Pathology Reconstruction in Preclinical Alzheimer's Disease

Previous research has emphasized the unique impact of Alzheimers Disease (AD) pathology on the medial temporal lobe (MTL), a reflection that tau pathology is particularly striking in the entorhinal and transentorhinal cortex (ERC, TEC) early in the course of disease. However, other brain regions are affected by AD pathology during its early phases. Here, we use longitudinal diffeomorphometry to measure the atrophy rate from MRI of the amygdala compared with that in the ERC and TEC in controls, individuals who progressed from normal cognition to mild cognitive impairment (MCI), and individuals with MCI who progressed to AD dementia, using a dataset from the Alzheimers Disease Neuroimaging Initiative (ADNI). Our results show significantly higher atrophy rates of the amygdala in both preclinical and MCI converters compared to controls, with rates of volume loss comparable to rates of thickness loss in the ERC and TEC. Using our recently developed method, referred to as Projective LDDMM, we map measures of neurofibrillary tau tangles (NFTs) from digital pathology to MRI atlases and reconstruct, for the first time, dense 3D spatial distributions of NFT density within regions of the MTL. The distribution of NFTs is consistent with the MR atrophy rates, revealing high densities not only in ERC, but in the amygdala and rostral third of the MTL. The similarity of the location of NFTs and shape changes in a well-defined clinical population suggests that amygdalar atrophy rate, as measured through MRI may be a viable biomarker for AD. PACS0000, 1111 2000 MSC0000, 1111 HighlightsO_LIAmygdala atrophy rate estimated from MRIs in preclinical Alzheimers disease (AD) C_LIO_LI3D distributions of neurofibrillary tau tangles (NFTs) reconstructed from 2D histology C_LIO_LINFTs highest in the rostral medial temporal lobe, including amygdala and ERC C_LIO_LIAmygdala atrophy rate is comparable to ERC atrophy rate in preclinical AD C_LIO_LIAmygdala and ERC atrophy rates as potential biomarkers rooted in NFT pathology C_LI

bioengineering↗

bioRxiv2022

Projective LDDMM: Spatially Reconstructing a Story of Rostrally-Dominant Tau in Alzheimer's Disease

Since Braaks initial histological observations, it has been recognized that Alzheimers disease (AD) neurofibrillary tangles (NFTs) appear in the medial temporal lobe (MTL) of the brain very early in the disease course. MRI-based shape diffeomorphometry markers have demonstrated pre-clinical AD changes in the MTL but it has not been possible to confirm that these MRI changes correspond to the presence of NFTs. Here, we present a method termed Projective LDDMM for aligning sparse measurement profiles of AD pathology (i.e., 2D digital histology images) with 3D MRI. We reconstruct measures of 2D NFT density in the dense metric of 3D MRI, using the Mai Paxinos Atlas coordinates for two cases of advanced AD. Analyses reveal the highest levels of NFT density in the rostral third (10-15 mm) of the hippocampus and the adjoining regions of the entorhinal cortex and amygdala. These findings emphasize the selective vulnerability of MTL subregions in AD, and suggest that high resolution MRI methods might benefit from focusing on the rostral MTL to more closely link these MRI images to AD neuropathology.

bioengineering↗

bioRxiv2022

The X chromosome is a potential polarising signal for asymmetric cell divisions in meiotic cells of a nematode

The unequal partition of molecules and organelles during cell division results in daughter cells with different fates. Asymmetric cell divisions have been best characterised in systems in which extrinsic signals polarise the mother cell during cell division. However, the mechanisms of asymmetric cell division mediated by intrinsic signals, and the nature of these signals, are mostly unknown. Here we report an asymmetric cell division in the nematode Auanema rhodensis that may be cued by the X chromosome. In the wildtype XO male, the spermatocyte divides asymmetrically to generate X-bearing spermatids that inherit components necessary for sperm viability, and nullo-spermatids that inherits components to be discarded. We found that in XX mutant pseudomales, sperm components co-segregate with the X chromosome, supporting the hypothesis that the X chromosome is employed as a polarising signal for partitioning essential cytoplasmic components for sperm function.

developmental biology↗

bioRxiv2022

In vivo correction of cystic fibrosis mediated by PNA nanoparticles

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We sought to correct the multiple organ dysfunction of the F508del CF-causing mutation using systemic delivery of peptide nucleic acid gene editing technology mediated by biocompatible polymeric nanoparticles. We confirmed phenotypic and genotypic modification in vitro in primary nasal epithelial cells from F508del mice grown at air-liquid interface and in vivo in F508del mice following intravenous delivery. In vivo treatment resulted in a partial gain of CFTR function in epithelia as measured by in situ potential differences and Ussing chamber assays and correction of CFTR in both airway and GI tissues with no off-target effects above background. This is the first report of systemic gene editing for CF. Our data suggest that systemic delivery of PNA NPs designed to correct CF-causing mutations is a viable option to ameliorate the disease in multiple affected organs.

bioengineering↗

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↗

bioRxiv2020

SNPC-1.3 is a sex-specific transcription factor that drives male piRNA expression in C. elegans

Piwi-interacting RNAs (piRNAs) play essential roles in silencing repetitive elements to promote fertility in metazoans. Studies in worms, flies, and mammals reveal that piRNAs are expressed in a sex-specific manner. However, the mechanisms underlying this sex-specific regulation are unknown. Here we identify SNPC-1.3, a variant of a conserved subunit of the snRNA activating protein complex, as a male-specific piRNA transcription factor in C. elegans. Binding of SNPC-1.3 at male piRNA loci drives spermatogenic piRNA transcription and requires the core piRNA transcription factor SNPC-4. Loss of snpc-1.3 leads to depletion of male piRNAs and defects in male-dependent fertility. Furthermore, TRA-1, a master regulator of sex determination, binds to the snpc-1.3 promoter and represses its expression during oogenesis. Loss of TRA-1 targeting causes ectopic expression of snpc-1.3 and male piRNAs during oogenesis. Thus, sexual dimorphic regulation of snpc-1.3 coordinates male and female piRNA expression during germline development.

developmental biology↗

bioRxiv2020

Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses

Missense mutations in the LRRK2 gene that lead to LRRK2 kinase hyperactivity can cause Parkinsons disease (PD). The link between LRRK2 and -synuclein aggregation in PD remains enigmatic. Numerous reports suggest critical LRRK2 functions in microglial responses. Herein, we find that LRRK2-positive immune cells in the brain represent CD68-positive pro-inflammatory, monocyte-derived macrophages, distinct from microglia. Rod -synuclein fibrils stimulate LRRK2 kinase activity in monocyte-derived macrophages, and LRRK2 mutations lead to enhanced recruitment of classical monocytes into the midbrain in response to -synuclein. LRRK2 kinase inhibition blocks -synuclein fibril induction of LRRK2 protein in both human and murine macrophages, with human cells demonstrating much higher LRRK2 levels and kinase activity than equivalent murine cells. Further, interferon-{gamma} strongly induces LRRK2 kinase activity in primary human macrophages in comparison to weak effects observed in murine cells. These results highlight peripheral immune responses in LRRK2-linked paradigms that further connect two central proteins in PD.

neuroscience↗

bioRxiv2020

Rab10 Regulates Macropinocytosis in Phagocytes

Genetic variation in LRRK2 associates with susceptibility to Parkinsons disease, Crohns disease, and mycobacteria infection, with high expression of LRRK2, and the LRRK2 kinase substrate Rab10, in phagocytic cells in the immune system. In mouse and human primary monocyte-derived macrophages, dendritic cells, and microglia-like cells, we find that Rab10 specifically regulates a specialized form of endocytosis known as macropinocytosis, without affecting phagocytosis or clathrin-mediated endocytosis. LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3-positive GTP-Rab10 early macropinosomes, before EEA1 and Rab5 recruitment occurs. Macropinosome cargo in macrophages includes CCR5, CD11b, and MHCII, with LRRK2-phosphorylation of Rab10 potently blocking EHBP1L1-mediated recycling tubules and cargo turnover. EHBP1L1 over-expression competitively inhibits LRRK2-phosphorylation of Rab10, mimicking the effects of LRRK2 kinase inhibition in promoting cargo recycling. Both Rab10 knockdown and LRRK2 kinase inhibition potently suppresses the maturation of macropinosome-derived CCR5-loaded signaling endosomes important for CCL5-induced AKT-activation and chemotaxis. These data support a novel axis in the endolysosomal system whereby LRRK2-mediated Rab10 phosphorylation stalls vesicle fast-recycling to promote PI3K-AKT signal transduction.

cell biology↗

bioRxiv2019

Enzalutamide-induced PTH1R-mediated TGFBR2 decrease in osteoblasts contributes to resistance in bone-metastatic prostate cancer

Over 80% of prostate cancer (PCa) patients in the United States die with bone metastases. Second-line hormonal therapies, such as enzalutamide, improve overall survival in about 50% of patients with bone metastases, but almost all responsive patients eventually develop enzalutamide resistance. Our study showed that although enzalutamide significantly inhibited the tumor growth of subcutaneously or orthotopically grafted PCa C4-2B cells, it had no effect on the bone lesion development when C4-2B tumors were grafted in the bone, suggesting a crucial role of the microenvironment in enzalutamide resistance in PCa bone metastasis. We found that enzalutamide significantly decreased the amount of the TGFBR2 (TGF-{beta} type II receptor) in osteoblasts, both in vitro and in patient samples. The osteoblast-specific knockout of Tgfbr2 significantly induced bone metastasis. We showed that the enzalutamide-induced TGFBR2 decrease in osteoblasts was mediated by increased PTH1R (parathyroid hormone/parathyroid hormone-related peptide receptor), which resulted in TGFBR2 degradation, and that blocking PTH1R rescued the TGFBR2 decrease. Furthermore, we found that PTH1R up-regulation by enzalutamide was correlated with increased Pth1r promoter occupancy by transcription factor NR2F1. Our findings highlight a potential enzalutamide-resistance mechanism through TGFBR2 decrease in osteoblasts, thus suggesting future PTH1R-blocking approaches to overcome enzalutamide resistance in PCa bone metastasis.

cancer biology↗

bioRxiv2019

A Cys2/His2 zinc finger protein acts as a repressor of gibberellins biosynthesis by regulating SD1/OsGA20ox2 in rice (Oryza sativa L.)

Gibberellins (GAs) play important roles in the regulation of plant growth and development. The green evolution gene SD1 encoding gibberellin 20-oxidase 2 (GA20ox2) has been widely used in modern rice breeding. However, the molecular mechanism of how SD1/OsGA20ox2 expression is regulated remains unclear. Here we report a Cys2/His2 zinc finger protein ZFP207 acting as a transcriptional repressor of OsGA20ox2. ZFP207 was mainly accumulated in young tissues and more specifically in culm nodes. ZFP207-overexpression (ZFP207OE) plants displayed semi-dwarfism phenotype and small grains by modulating cell length. RNA interference of ZFP207 caused higher plant and longer grains. The endogenous bioactive GA levels were significantly reduced in ZFP207OE plants and application of exogenous GA3 rescued the semi-dwarf phenotype. The in vivo and in vitro studies showed that ZFP207 repressed the expression of OsGA20ox2 via binding to its promoter region. Together, ZFP207 acts as a transcriptional repressor of gibberellins biosynthesis and it may play a critical role in plant growth and development through fine-tuning GA biosynthesis in rice.

molecular biology↗

bioRxiv2018

Mammalian stringent-like response mediated by the cytosolic NADPH phosphatase MESH1

Nutrient deprivation triggers stringent response in bacteria, allowing rapid reallocation of resources from proliferation toward stress survival. Critical to this process is the accumulation/degradation of (p)ppGpp regulated by the RelA/SpoT homologues. While mammalian genomes encode MESH1, a homologue of the bacterial (p)ppGpp hydrolase SpoT, neither (p)ppGpp nor its synthetase has been identified in mammalian cells. Therefore, the function of MESH1 remains a mystery. Here, we report that human MESH1 is an efficient cytosolic NADPH phosphatase, an unexpected enzymatic activity that is captured by the crystal structure of the MESH1-NADPH complex. MESH1 depletion promotes cell survival under ferroptosis-inducing conditions by sustaining the level of NADPH, an effect that is reversed by the simultaneous depletion of the cytosolic NAD(H) kinase, NADK, but not its mitochondrial counterpart NADK2. Importantly, MESH1 depletion also triggers extensive transcriptional changes that are distinct from the canonical integrated stress response but resemble the bacterial stringent response, implicating MESH1 in a previously uncharacterized stress response in mammalian cells.

biochemistry↗