Biology subjects

Chen, D.

Publications and source records attributed to Chen, D..

At least 325 records · Page 18Linked to original sources

bioRxiv2020

Deciphering the mechanism underlying circRNA-mediated immune responses of western honeybees to Nosema ceranae infection

Nosema ceranae is a widespread fungal parasite for adult honeybees, severely damaging bee health and sustainable development of apiculture. Circular RNAs (circRNAs) are a class of newly discovered noncoding RNAs (ncRNAs) that regulate a number of biological processes such as immune defense and development. In this current work, based on previously obtained whole transcriptome data, 8 199 and 8 711 circRNAs were predicted from the midguts of Apis mellifera ligustica workers at 7 days (AmT1) and 10 days (AmT2) post inoculation (dpi) with N. ceranae using bioinformatics. Additionally, in combination with transcriptome data from uninfected midguts (AmCK1 and AmCK2) (Xiong et al., 2018), 4 464 circRNAs were found to be shared by the aforementioned four groups, whereas the numbers of specifically transcribed circRNAs in each group were 1 389, 1 696, 1 019 and 1 871, respectively. Furthermore, 10 226 circRNAs were homologous to Apis cerana cerana circRNAs, while 20 circRNAs had homology with Homo sapiens circRNAs; in addition, 16 circRNAs were highly conserved in these three species. Differential expression analysis showed that 168 (306) differentially expressed circRNAs (DEcircRNAs) were identified in AmCK1 vs AmT1 (AmCK2 vs AmT2) comparison group, including 61 (143) upregulated circRNAs and 107 (163) downregulated circRNAs. Moreover, RT-qPCR results showed that the expression trend of eight DEcircRNAs was consistent with that of the transcriptome dataset. Based on GO database annotation, we observed that source genes of DEcircRNAs in AmCK1 vs AmT1 (AmCK2 vs AmT2) were engaged in 27 (35) functional terms, including two (two) cell renewal-associated terms, seven (seven) cell structure-associated terms, and one (one) immunity-associated terms. Additionally, DEcircRNA source genes in AmCK1 vs AmT1 were involved in two cell renewal-related pathways, Hippo and Wnt signaling pathways, and three carbohydrate metabolism-related pathways, galactose metabolism, starch and sucrose metabolism, fructose and mannose metabolism, only one energy metabolism-related pathway (oxidative phosphorylation pathway), three cellular immune-related pathways, endocytosis, phagosome, and lysosome, and a humoral immune-related pathway (FoxO signaling pathway). In AmCK2 vs AmT2 comparison group, more source genes of DEcircRNAs were associated with the abovementioned pathways relative to cell renewal, carbohydrate metabolism, and cellular and humoral immune pathways. In addition, 122 (234) DEcircRNAs in the host midgut at 7 dpi (10 dpi) with N. ceranae targeted 82 (106) miRNAs. Furthermore, 75 (103) miRNAs targeted by 86 (178) DEcircRNAs in AmCK1 vs AmT1 (AmCK2 vs AmT2) further bound to 215 (305) mRNAs. These targets could be annotated as an array of functional terms and pathways related to cellular renewal, cellular structure, carbohydrate and energy metabolism, and cellular and humoral immunity. In a word, we for the first time explored immune responses mediated by DEcircRNAs in the midguts of A. m. ligustica workers to N. ceranae infection. Our data provide a foundation for clarifying the molecular mechanism underlying immune response of western honeybee to N. ceranae invasion, but also a new insight into further understanding the host-pathogen interaction during bee microsporidiosis.

genomics↗

bioRxiv2020

Diversity and dynamics of fungi during spontaneous fermentations and association with unique aroma profiles in wine

Microbial activity is an integral part of an agricultural ecosystem and influences the quality of agricultural commodities. Microbial ecology influences grapevine health and crop production, conversion of sugar to ethanol during fermentation, thus wine aroma and flavour. There are regionally differentiated microbial patterns in grapevines and must but how microbial patterns contribute to wine regional distinctiveness (terroir) at small scale (<100 km) is not well defined. Here we characterise fungal communities, yeast populations, and Saccharomyces cerevisiae populations during spontaneous fermentation using metagenomics and population genetics to investigate microbial distribution and fungal contributions to the resultant wine. We found differentiation of fungi, yeasts, and S. cerevisiae between geographic origins (estate/vineyard), with influences from the grape variety. Growth and dominance of S. cerevisiae during fermentation reshaped the fungal community and showed geographic structure at the strain level. Associations between fungal microbiota diversity and wine chemicals suggest that S. cerevisiae plays a primary role in determining wine aroma profiles at a sub-regional scale. The geographic distribution at scales of less than 12 km supports that differential microbial communities, including the dominant fermentative yeast S. cerevisiae can be distinct in a local setting. These findings provide further evidence for microbial contributions to wine terroir, and perspectives for sustainable agricultural practices to maintain microbial diversity and optimise fermentation function to craft beverage quality.

microbiology↗

bioRxiv2020

Discovery of a Potent and Dual-Selective Bisubstrate Inhibitor for Protein Arginine Methyltransferase 4/5

Protein arginine methyltransferases (PRMTs) have been implicated in the progression of many diseases. Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery. Herein, we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine (SAM) analogue moiety and a tripeptide through an alkyl substituted guanidino group. Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration (IC50) of 2.8 nM and <1.5 nM, respectively. Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases. This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs, providing valuable probes for future structural studies.

biochemistry↗

bioRxiv2020

Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses

T cell metabolic fitness plays a pivotal role in anti-tumor immunity and metabolic deregulation causes T cell dysfunction (i.e., exhaustion) in cancer. We identify that the scavenger receptor CD36 limits anti-tumor CD8+ T cell effector functions through lipid peroxidation. In murine tumors, oxidized phospholipids (OxPLs) were highly abundant and CD8+ TILs increased uptake and accumulation of lipids and lipid peroxidation. Functionally exhausted CD8+ TILs substantially increased CD36 expression and CD36-deficient CD8+ TILs had more robust anti-tumor activity and cytokine production than wild-type cells. We further show that CD36 promotes uptake of oxidized low-density lipoproteins (OxLDL) and induces lipid peroxidation in CD8+ TILs, and OxLDL inhibits CD8+ T cell functions in a CD36-dependent manner. Moreover, glutathione peroxidase 4 (GPX4) over-expression lowers lipid peroxidation and restores functionalities in CD8+ TILs. These results define a key role for an oxidized lipid-CD36 axis in promoting intratumoral CD8+ T cell dysfunction.

immunology↗

bioRxiv2020

Distinct effects of different matrix proteoglycans on collagen fibrillogenesis and cell-mediated collagen reorganization

The extracellular matrix (ECM) is a complex mixture composed of fibrillar collagens as well as additional protein and carbohydrate components. Proteoglycans (PGs) contribute to the heterogeneity of the ECM and play an important role in its structure and function. While the small leucine rich proteoglycans (SLRPs), including decorin and lumican, have been studied extensively as mediators of collagen fibrillogenesis and organization, the function of large matrix PGs in collagen matrices is less well known. In this study, we showed that different matrix PGs have distinct roles in regulating collagen behaviors. We found that versican, a large chondroitin sulfate PG, promotes collagen fibrillogenesis in a turbidity assay and upregulates cell-mediated collagen compaction and reorganization, whereas aggrecan, a structurally-similar large PG, has different and often opposing effects on collagen. Compared to versican, decorin and lumican also have distinct functions in regulating collagen behaviors. The different ways in which matrix PGs interact with collagen have important implications for understanding the role of the ECM in diseases such as fibrosis and cancer, and suggest that matrix PGs are potential therapeutic targets. HighlightsO_LISmall leucine rich proteoglycans (SLRPs) and large chondroitin sulfate (CS) proteoglycans (PGs) have distinct effects on collagen fibrous network behavior. C_LIO_LIUnlike other matrix proteoglycans, versican promotes collagen fibrillogenesis in an in vitro spectrophotometric (turbidity) assay. C_LIO_LIThe versican core protein has a larger impact on collagen behavior in a fibrillogenesis assay than its glycosaminoglycan chains do. C_LIO_LIVersican increases the diameter of collagen fibers and the porosity of collagen fibrous networks, unlike aggrecan and SLRPs. C_LIO_LIThe addition of versican to collagen does not alter fibroblast contractility but leads to enhanced cell-mediated collagen reorganization and contraction. C_LI

cell biology↗

bioRxiv2020

Distinct roles of two RDL GABA-receptors in fipronil action in the diamondback moth (Plutella xylostella)

The phenylpyrazole insecticide, fipronil, blocks insect RDL {gamma}-aminobutyric acid (GABA) receptors, thereby impairs inhibitory neurotransmission. Some insect species, such as the diamondback moth (Plutella xylostella), possess more than one Rdl gene. The involvement of multiple Rdls in fipronil toxicity and resistance remain largely unknown. In this study, we investigated the roles of two Rdl genes, PxRdl1 and PxRdl2, from P. xylostella in the action of fipronil. Expressed in Xenopus oocytes, PxRDL2 receptors were 40-times less sensitive to fipronil than PxRDL1. PxRDL2 receptors were also less sensitive to GABA compared to PxRDL1. Knockout of the fipronil-sensitive PxRdl1 gene reduced the potency of fipronil by 10 fold, whereas knockout of the fipronil-resistant PxRdl2 gene enhanced the potency of fipronil by 4.4 fold. Furthermore, in two fipronil-resistant diamondback moth field populations, the expression of PxRdl2 was elevated by 3.7-fold and 4.1-fold, respectively compared to a susceptible strain, whereas the expression of PxRdl1 was comparable among the resistant and susceptible strains. Collectively, our results indicate antagonistic effects of PxRDL1 and PxRDL2 on the fipronil action in vivo and suggest enhanced expression of fipronil-resistant PxRdl2 potentially a new mechanism of fipronil resistance in insects.

molecular biology↗

bioRxiv2020

The molecular taxonomy of primate amygdala via single-nucleus RNA-sequencing analysis

Amygdala is the central brain region governing emotional responses of mammals. However, the detailed molecular taxonomy of amygdala in higher mammals such as primates is still absent. Here we present the molecular taxonomy of amygdala in rhesus monkeys by single-cell RNA sequencing analysis. We found that there are five major cell types in primate amygdala, glutamatergic neurons, GABAergic neurons, astroglia, oligodendrocytes and oligodendrocyte progenitor cells (OPCs). Glutamatergic neurons in the primate amygdala exhibits a great diversity comparing to them in the rodent amygdala. In particular, GABAergic neurons in primate amygdala appeared to be quite unique and contain different cellular composition as them in rodent amygdala. The astroglia in primate amygdala contains two more subtypes comparing to astroglia in rodent amygdala. Taken together, although the evolutionary conservation, the molecular taxonomy study of primate amygdala provides critical insights for understanding the cellular architecture of the primate brain.

neuroscience↗

bioRxiv2020

A Multi-Phenotype System to Discover Therapies for Age-Related Dysregulation of the Immune Response to Viral Infections

Age-related immune dysregulation contributes to increased susceptibility to infection and disease in older adults. We combined high-throughput laboratory automation with machine learning to build a multi-phenotype aging profile that models the dysfunctional immune response to viral infection in older adults. From a single well, our multi-phenotype aging profile can capture changes in cell composition, physical cell-to-cell interaction, organelle structure, cytokines, and other hidden complexities contributing to age-related dysfunction. This system allows for rapid identification of new potential compounds to rejuvenate older adults immune response. We used our technology to screen thousands of compounds for their ability to make old immune cells respond to viral infection like young immune cells. We observed beneficial effects of multiple compounds, of which two of the most promising were disulfiram and triptonide. Our findings indicate that disulfiram could be considered as a treatment for severe coronavirus disease 2019 and other inflammatory infections.

immunology↗

bioRxiv2020

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.

immunology↗

bioRxiv2020

BDdb: a comprehensive platform for exploration and utilization of birth defect multi-omics data

Birth defect, not only poses a major challenge for infant health but also attracts the attention of countless people in the world. Chromosome abnormality directly results in diverse birth defects which are generally deleterious and even lethal. Therefore, gaining molecular regulatory insights into these diseases is important and necessary for effective prenatal screening. Recently, with the advance of next-generation sequencing (NGS) techniques, a myriad of treatises and data associated with these diseases are now constantly produced from different laboratories across the world. To meet the increasing requirements for birth-related data resources, we developed a birth defect multi-omics database (BDdb), freely accessible at http://t21omics.cngb.org and consisting of multi-omics data, circulating free DNA (cfDNA) data, as well as diseases biomarkers. Omics data sets from 138 GSE samples, 5271 GSM samples and 328 entries, and more than 2000 biomarkers of 22 birth-defect diseases in 5 different species were integrated into BDdb, which provides a user-friendly interface for searching, browsing and downloading selected data. Additionally, we re-analyzed and normalized the raw data so that users can also customize the analysis using the data generated from different sources or different High-Throughput Sequencing (HTS) methods. To our knowledge, BDdb is the first comprehensive database associated with birth-defect-related diseases. which would benefit the diagnosis and prevention of birth defects.

bioinformatics↗

bioRxiv2020

Peramivir, an anti-influenza virus drug, exhibits potential anti-cytokine storm effects

Coronavirus Disease 2019 (COVID-19) infected by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been declared a public health emergency of international concerns. Cytokine storm syndrome (CSS) is a critical clinical symptom of severe COVID-19 patients, and the macrophage is recognized as the direct host cell of SARS-CoV-2 and potential drivers of CSS. In the present study, peramivir was identified to reduce TNF- by partly intervention of NF-{kappa}B activity in LPS-induced macrophage model. In vivo, peramivir reduced the multi-cytokines in serum and bronchoalveolar lavage fluid (BALF), alleviated the acute lung injury and prolonged the survival time in mice. In human peripheral blood mononuclear cells (hPBMCs), peramivir could also inhibit the release of TNF-. Collectively, we proposed that peramivir might be a candidate for the treatment of COVID-19 and other infections related CSS. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/201806v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@667e34org.highwire.dtl.DTLVardef@e7bf85org.highwire.dtl.DTLVardef@ced400org.highwire.dtl.DTLVardef@c055a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Dental ontogeny in the most primitive bony fish Lophosteus reveals the developmental relationship between teeth and dermal odontodes

Ontogenetic data obtained by synchrotron microtomography of a marginal jawbone of Lophosteus superbus (Late Silurian, 422 Million years old), the phylogenetically basalmost stem osteichthyan, reveal developmental relationships between teeth and ornament that are not obvious from the adult morphology. The earliest odontodes are two longitudinal founder ridges formed at the ossification center. Subsequent odontodes that are added lingually to the ridges turn into conical teeth and undergo cyclic replacement, while those added labially achieve a stellate appearance. The stellate odontodes deposited directly on the bony plate are aligned with the alternate files of the teeth. Successive odontodes overgrowing the labial tooth rows become tooth-like and the replacement teeth near to them are ornament-like. We propose that teeth and ornament are modifications of a single odontode system regulated and differentiated by the oral and dermal signals; signal cross-communication between the two domains can occur around the oral-dermal boundary.

evolutionary biology↗

bioRxiv2020

Inferring cellular trajectories from scRNA-seq using Pseudocell Tracer

Single cell RNA sequencing (scRNA-seq) can be used to infer a temporal ordering of dynamic cellular states. Current methods for the inference of cellular trajectories rely on unbiased dimensionality reduction techniques. However, such biologically agnostic ordering can prove difficult for modeling complex developmental or differentiation processes. The cellular heterogeneity of dynamic biological compartments can result in sparse sampling of key intermediate cell states. This scenario is especially pronounced in dynamic immune responses of innate and adaptive immune cells. To overcome these limitations, we develop a supervised machine learning framework, called Pseudocell Tracer, which infers trajectories in pseudospace rather than in pseudotime. The method uses a supervised encoder, trained with adjacent biological information, to project scRNA-seq data into a low-dimensional cellular state space. Then a generative adversarial network (GAN) is used to simulate pesudocells at regular intervals along a virtual cell-state axis. We demonstrate the utility of Pseudocell Tracer by modeling B cells undergoing immunoglobulin class switch recombination (CSR) during a prototypic antigen-induced antibody response. Our results reveal an ordering of key transcription factors regulating CSR, including the concomitant induction of Nfkb1 and Stat6 prior to the upregulation of Bach2 expression. Furthermore, the expression dynamics of genes encoding cytokine receptors point to the existence of a regulatory mechanism that reinforces IL-4 signaling to direct CSR to the IgG1 isotype.

bioinformatics↗

bioRxiv2020

PacC-dependent adaptation and modulation of host cellular pH controls hemibiotrophic invasive growth and disease development by the rice blast fungus

Many of the worlds most serious crop diseases are caused by hemibiotrophic fungi. These pathogens have evolved the ability to colonize living plant cells, suppressing plant immunity responses, before switching to necrotrophic growth, in which host cells die, providing the energy to fuel sporulation and spread of the fungus. How hemibiotrophic pathogens switch between these two lifestyles remains poorly understood. Here, we report that the devastating rice blast fungus, Magnaporthe oryzae, manipulates host cellular pH to regulate hemibiotrophy. During infection by M. oryzae, host plant cells are alkalinized to pH 7.8 during biotrophic growth, but later acidified to pH 6.5 during necrotrophy. Using a forward genetic screen, we identified alkaline-sensitive mutants of M. oryzae that were blocked in biotrophic proliferation and impaired in induction of host cell acidification and necrotrophy. These mutants defined components of the PacC-dependent ambient pH signal transduction pathway in M. oryzae. We report that PacC exists as a full-length repressor, PacC559, and a truncated transcriptional activator, PacC222, which localize to the fungal nucleus during biotrophic growth and to the cytoplasm during necrotrophy. During biotrophy, PacC222 directly activates genes associated with nutrient acquisition and fungal virulence, while PacC559 represses genes associated with saprophytic mycelial growth and sporulation, which are subsequently de-repressed during necrotrophy. When considered together, our results indicate that temporal regulation of hemibiotrophy by M. oryzae requires PacC-dependent sensing and manipulation of host cellular pH. Author SummaryCrop diseases caused by fungi represent some of the most serious threats to global food security. Many fungal pathogens have evolved the ability to invade living plant tissue and suppress host immunity, before switching to a completely different mode of growth, in which they are able to kill host plant cells. This lifestyle- called hemibiotrophy -is exemplified by the blast fungus, Magnaporthe oryzae, which causes devastating diseases of rice, wheat and many other grasses. We found that during infection by M. oryzae, host cells initially have an alkaline pH, when the fungus is growing in living tissue, but pH rapidly becomes acidic, as host tissue is killed. We identified mutants of the blast fungus that were sensitive to alkaline pH and this enabled us to identify the signal transduction pathway by which the fungus responds to changes in ambient pH. We found that mutants in the pH response pathway were blocked in invasive fungal growth and could not cause acidification of host tissue. Consequently, they are unable to cause blast disease. We characterized the central regulator of this pathway, the PacC transcription factor, which unusually can act as both a repressor and an activator of fungal gene expression. During biotrophic invasive growth, PacC activates many genes previously reported to be required for virulence, including several associated with nutrient acquisition, and at the same time represses genes associated with vegetative growth and sporulation. The PacC signaling pathway is therefore necessary for regulating the switch in fungal lifestyle associated with causing blast disease.

microbiology↗

bioRxiv2020

A system for phenotype harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institutes Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 TOPMed studies per phenotype. We discuss the challenges faced in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

genetics↗

bioRxiv2020

Single-cell screening of SARS-CoV-2 target cells in pets, livestock, poultry and wildlife

A few animals have been suspected to be intermediate hosts of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a large-scale single-cell screening of SARS-CoV-2 target cells on a wide variety of animals is missing. Here, we constructed the single-cell atlas for 11 representative species in pets, livestock, poultry, and wildlife. Notably, the proportion of SARS-CoV-2 target cells in cat was found considerably higher than other species we investigated and SARS-CoV-2 target cells were detected in multiple cell types of domestic pig, implying the necessity to carefully evaluate the risk of cats during the current COVID-19 pandemic and keep pigs under surveillance for the possibility of becoming intermediate hosts in future coronavirus outbreak. Furthermore, we screened the expression patterns of receptors for 144 viruses, resulting in a comprehensive atlas of virus target cells. Taken together, our work provides a novel and fundamental strategy to screen virus target cells and susceptible species, based on single-cell transcriptomes we generated for domesticated animals and wildlife, which could function as a valuable resource for controlling current pandemics and serve as an early warning system for coping with future infectious disease threats.

cell biology↗

bioRxiv2020

Bridging scales in scattering tissues via multifocal two-photon microscopy

Imaging biological systems at subcellular resolution and across scales is essential to under-standing how cells form tissues, organs, and organisms. However, existing large-scale optical techniques often require harsh tissue-clearing methods that cause significant morphological changes, compromise the integrity of cell membranes, and reduce the signal of fluorescent proteins. Here, we demonstrate multifocal two-photon microscopy that enables imaging mesoscopic scattering samples in their native tissue environment at high resolution and high speed.

bioengineering↗

bioRxiv2020

HAP40 is a conserved central regulator of Huntingtin and a specific modulator of mutant Huntingtin toxicity

Perturbation of Huntingtin (HTT)s physiological function is one postulated pathogenic factor in Huntingtons disease (HD). However, little is known how HTT is regulated in vivo. In a proteomic study, we isolated a novel [~]40kDa protein as a strong binding partner of Drosophila HTT and demonstrated it was the functional ortholog of HAP40, an HTT associated protein shown recently to modulate HTTs conformation but with unclear physiological and pathologic roles. We showed that in both flies and human cells, HAP40 maintained conserved physical and functional interactions with HTT, loss of HAP40 resulted in similar phenotypes as HTT knockout, including animal viability and autophagy, and more strikingly, HAP40 depletion significantly reduced the levels of endogenous HTT, while HAP40 was mostly degraded via the proteasome in the absence of HTT. Interestingly, polyglutamine expansion in HTT did not affect its affinity for HAP40. However, HAP40 modulated HD pathogenesis in Drosophila model by regulating the overall protein levels and the toxicity of full-length mutant HTT. Together, our study uncovers a conserved mechanism governing the stability and in vivo functions of HTT, and demonstrates that HAP40 is a central and positive regulator of HTT, a potential modulator of HD pathogenesis and a promising candidate for "HTT-lowering" strategy against HD.

neuroscience↗