Biology subjects

Yin, S.

Publications and source records attributed to Yin, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

PHOSPHATE-INDUCED 1 and its paralogs positively regulate cellulose biosynthesis in Arabidopsis.

Cellulose is not only the most abundant biopolymer on Earth but also an essential multi-purpose resource, primarily synthesized by cellulose synthase complexes (CSCs) located on plasma membrane in vascular plants. Although insights into the functions of CSCs have been provided by the identification of cellulose synthase catalytic subunits, our understanding of the regulation of CSC activity remains limited. In this study, combining molecular and genetic methods, we demonstrated that both PHI-1 and its paralogs residing in the plasma membrane are involved in the cellulose biosynthesis regulation as a positive regulatory component of CSCs by feeding developmental and environmental cues into their activities in Arabidopsis (Arabidopsis thaliana). Our finding reveals a mechanism for how plants regulate cellulose synthesis in response to developmental and environmental signals, and thus improves the likelihood that cellulose biosynthesis could be feasibly adapted for sustainable purposes.

plant biology↗

bioRxiv2024

Targeting resident astrocytes attenuates neuropathic pain after spinal cord injury

Astrocytes derive from different lineages and play a critical role in neuropathic pain after spinal cord injury (SCI). Whether selective eliminating these main origins of astrocytes in lumbar enlargement could attenuate SCI-induced neuropathic pain remains unclear. Through transgenic mice injected with an adeno-associated virus vector and diphtheria toxin, astrocytes in lumbar enlargement were lineage traced, targeted and selectively eliminated. Pain-related behaviors were measured with an electronic von Frey apparatus and a cold/hot plate after SCI. RNA sequencing, bioinformatics analysis, molecular experiment and immunohistochemistry were used to explore the potential mechanisms after astrocyte elimination. Lineage tracing revealed that the resident astrocytes but not ependymal cells were the main origins of astrocytes-induced neuropathic pain. SCI induced mice to obtain significant pain symptoms and astrocyte activation in lumbar enlargement. Selective resident astrocytes elimination in lumbar enlargement could attenuate neuropathic pain and activate microglia. Interestingly, the type I interferons (IFNs) signal was significantly activated after astrocytes elimination, and the most activated Gene Ontology terms and pathways were associated with the type I IFNs signal which was mainly activated in microglia and further verified in vitro and in vivo. Furthermore, different concentrations of interferon and Stimulator of interferon genes (STING) agonist could activate the type I IFNs signal in microglia. These results elucidate that selectively eliminating resident astrocytes attenuated neuropathic pain associated with type I IFNs signal activation in microglia. Targeting type I IFNs signal is proven to be an effective strategy for neuropathic pain treatment after SCI.

neuroscience↗

bioRxiv2023

Oncogenic PIK3CA corrupts growth factor signaling specificity

Pathological activation of the PI3K/AKT pathway is among the most frequent defects in human cancer and is also the cause of rare overgrowth disorders. Yet, there is currently no systematic understanding of the quantitative flow of information within PI3K/AKT signaling and how it is perturbed by disease-causing mutations. Here, we develop scalable, single-cell approaches for systematic analyses of signal processing within the PI3K pathway, enabling precise calculations of its information transfer for different growth factors. Using genetically-engineered human cell models with allele dose-dependent expression of PIK3CAH1047R, we show that this oncogene is not a simple, constitutive pathway activator but a context-dependent modulator of extracellular signal transfer. PIK3CAH1047Rreduces information transmission downstream of IGF1 while selectively enhancing EGF-induced signaling and transcriptional responses. This leads to a gross reduction in signaling specificity, akin to "blurred" signal perception. The associated increase in signaling heterogeneity promotes phenotypic diversity in a human cervical cancer cell line model and in human induced pluripotent stem cells. Collectively, these findings and the accompanying methodological advances lay the foundations for a systematic mapping of the quantitative mechanisms of PI3K/AKT-dependent signal processing and phenotypic control in health and disease. One-sentence summarySingle-cell signaling and information theoretic analyses reveal that oncogenic PI3K/AKT activation leads to a gross reduction in signaling specificity, context-dependent EGF response amplification as well as increased phenotypic heterogeneity.

systems biology↗

bioRxiv2023

A molecularly distinct cell type in the dmPAG regulates intermale aggression behaviors in mice

BackgroundThe periaqueductal gray (PAG) is a central hub for regulation of aggression, while little is known on the circuitry and molecular mechanisms that govern this regulation. We investigate the role of a distinct cell type, Tachykinin 2-expressing (Tac2+) neurons, located in the dorsomedial PAG (dmPAG), in modulating aggression in mice. MethodsWe combined activity mapping, in vivo Ca2+ recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model. ResultsWe reveal that the dmPAGTac2 neurons were selectively activated during fighting behaviors. Activation of the dmPAGTac2 neurons evoked, while inhibition or genetic ablation of the dmPAGTac2 neurons suppressed fighting behaviors. TRAP profiling of dmPAGTac2 neurons revealed that fighting behaviors specifically induced enrichment of serotonin-associated transcripts to the dmPAGTac2 neurons. Last, we validated these findings by selectively delivering pharmacological agent into the dmPAG and reversed the behavioral outcomes induced by chemogenetic manipulation. ConclusionsWe identify that the dmPAGTac2 neuron can regulate mouse aggressive behavior and thus suggest a distinct molecular target for the treatment of exacerbated aggressive behaviors in populations that exhibit high-level of violence. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/562724v3_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@afc876org.highwire.dtl.DTLVardef@91e355org.highwire.dtl.DTLVardef@1e41e43org.highwire.dtl.DTLVardef@17ef3f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

SARS-CoV-2 Omicron infection augments the magnitude and durability of systemic and mucosal immunity in triple-dose CoronaVac recipients

BackgroundThe inactivated whole-virion vaccine, CoronaVac, is one of the most widely used coronavirus disease 2019 (COVID-19) vaccines worldwide. There is a paucity of data indicating the durability of the immune response and the impact of immune imprinting induced by CoronaVac upon Omicron breakthrough infection. MethodsIn this prospective cohort study, 41 recipients of triple-dose CoronaVac and 14 unvaccinated individuals were recruited. We comprehensively profiled adaptive immune parameters in both groups, including spike-specific immunoglobulin (Ig) G and IgA titers, neutralizing activity, B cells, follicular helper T (Tfh) cells, CD4+ and CD8+ T cells, and their memory subpopulations at 12 months after the third booster dose and at 4 weeks and 20 weeks after Omicron BA.5 infection. ResultsTwelve months after the third CoronaVac vaccination, spike-specific antibody and cellular responses were detectable in most vaccinated individuals. BA.5 infection significantly augmented the magnitude, cross-reactivity and durability of serum neutralization activities, Fc-mediated phagocytosis, and nasal spike-specific IgA responses, memory B cells, activated Tfh cells memory CD4+ T cells, and memory CD8+ T cells for both the ancestral strain and Omicron subvariants, compared to unvaccinated individuals. Notably, the increase in BA.5-specific immunity after breakthrough infection was consistently higher than for the ancestral strain, suggesting no evidence of immune imprinting. Immune landscape analyses showed vaccinated individuals have better synchronization of multiple immune components than unvaccinated individuals upon heterologous SARS-CoV-2 infection. ConclusionOur data provides detailed insight into the protective role of inactivated COVID-19 vaccine in shaping humoral and cellular immune responses to heterologous Omicron infection. Trial registrationClinicalTrials.gov NCT05680896 FundingThis study was supported by the National Natural Science Foundation of China (92269118, 92269205), Nanjing Important Science & Technology Specific Projects (2021-11005), Scientific Research Project of Jiangsu Health Commission (M2022013), Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (2021-LCYJ-PY-9), and Jiangsu graduate practice innovation project (JX22013929).

immunology↗

bioRxiv2023

Post-Mating Inhibition of Female Sexual Drive via Heterogeneous Neuronal Ensembles in the Medial Preoptic Area

Male ejaculation acutely suppresses sexual motivation in male mice. In contrast, relatively little is known about how male ejaculation affects sexual motivation and sexual behavior in female mice. How the brain responds to completion of mating is also unclear. Here, by using self-paced mating assay, we first demonstrate that female mice show decreased sexual motivation acutely after experiencing male ejaculation. By using brain-wide analysis of activity-dependent labeling, we next pinpointed the medial preoptic area as a brain region strongly activated during the post-ejaculatory period. Furthermore, using freely moving in vivo calcium imaging to compare neural activity of inhibitory and excitatory neurons in the medial preoptic area, we revealed that a subset of the neurons in this region respond significantly and specifically to male ejaculation but not to female-to-male sniffing or to male mounting. While there were excitatory and inhibitory neurons that showed increased response to male ejaculation, the response magnitude as well as the proportion of neurons responding to the event was significantly larger in the inhibitory neuron population. Next, by unbiased classification of their responses, we also found a subpopulation of neurons that increase their activity late after the onset of male ejaculation. These neurons were all inhibitory indicating that male ejaculation induces a prolonged inhibitory activity in the medial preoptic area. Lastly, we found that chemogenetic activation of medial preoptic area neurons that were active during post-ejaculatory period, but not during appetitive or consummatory periods, were sufficient to suppress female sexual motivation. Together, our data illuminate the importance of medial preoptic area as a brain node which encodes a negative signal that sustains low sexual motivation state after the female mice experience ejaculation. HighlightsO_LIFemale mice show decreased sexual motivation in the post-ejaculatory period. C_LIO_LIA subset of MPOA neurons in female respond specifically to male ejaculation. C_LIO_LIMale-ejaculation evokes persistent activity in MPOA inhibitory neurons in females. C_LIO_LIActivation of a subset of MPOA neurons is sufficient to suppress female sexual motivation. C_LI

neuroscience↗

bioRxiv2023

Histone chaperone HIRA, Promyelocytic Leukemia (PML) protein and p62/SQSTM1 coordinate to regulate inflammation during cell senescence and aging.

Cellular senescence, a stress-induced stable proliferation arrest associated with an inflammatory Senescence-Associated Secretory Phenotype (SASP), is a cause of aging. In senescent cells, Cytoplasmic Chromatin Fragments (CCFs) activate SASP via the anti-viral cGAS/STING pathway. PML protein organizes PML nuclear bodies (NBs), also involved in senescence and anti-viral immunity. The HIRA histone H3.3 chaperone localizes to PML NBs in senescent cells. Here, we show that HIRA and PML are essential for SASP expression, tightly linked to HIRAs localization to PML NBs. Inactivation of HIRA does not directly block expression of NF-{kappa}B target genes. Instead, an H3.3-independent HIRA function activates SASP through a CCF-cGAS-STING-TBK1-NF-{kappa}B pathway. HIRA physically interacts with p62/SQSTM1, an autophagy regulator and negative SASP regulator. HIRA and p62 co-localize in PML NBs, linked to their antagonistic regulation of SASP, with PML NBs controlling their spatial configuration. These results outline a role for HIRA and PML in regulation of SASP.

cell biology↗

bioRxiv2023

Functional Relations of CSLD2, CSLD3, and CSLD5 Proteins during Cell Wall Synthesis in Arabidopsis

Plant cell expansion is a dynamic process that is physically constrained by the deposition of new cell wall components. During tip growth, new cell wall materials are delivered at a restricted plasma membrane domain which results in a highly polarized expansion within that specified domain. Previous studies demonstrated that this process requires the activities of members of the Cellulose Synthase-Like D (CSLD) subfamily of cell wall synthases. CSLD3 displays {beta}-1,4 glucan synthase activity, but whether other members of CSLD subfamily share this conserved biochemical activity, and whether CSLD proteins form higher-order complexes to perform {beta}-1,4 glucan synthase activities have not been determined. Here, we use genetic methods to demonstrate that CSLD2 and CSLD3 functions are interchangeable during root hair elongation and cell plate formation, while CSLD5 provides a unique and irreplaceable function in the formation of cell plates. Importantly, genetic analysis with inactivated versions of CSLD3 show that, unlike CESA proteins, CSLDs do not require the simultaneous presence of different isoforms to perform catalytic cell wall synthase activities. In vitro biochemical activity experiments confirmed that CSLD2, CSLD3, and CSLD5 proteins displayed {beta}-1,4 glucan synthases activities. Taken together, these results indicated that while all three vegetatively expressed CSLD proteins possess conserved {beta}-1,4 glucan synthase activities, that CSLD5 has a more complicated and specialized role during cell plate formation.

cell biology↗

bioRxiv2023

Hox genes modulate physical forces to differentially shape small and large intestinal epithelia

The small and large intestines arise from a common primordial gut tube but ultimately become specialized in both form and function. While the midgut forms villi, the hindgut develops flat, brain-like sulci that resolve into heterogeneous outgrowths. Gut compartment identities are demarcated early in development via Hox genes, which are highly conserved, master regulators of spatial patterning in the embryo. Yet, how these factors trigger regional morphogenesis has remained a mystery. Combining mechanical measurements and mathematical modeling, we demonstrate that the posterior Hox gene Hoxd13 regulates biophysical phenomena that shape the hindgut lumen. We further show that Hoxd13 acts through the TGF{beta} pathway to thicken, stiffen, and promote isotropic growth of the subepithelial mesenchyme; together, these features generate hindgut surface patterns. TGF{beta}, in turn, promotes collagen deposition to affect mesenchymal geometry and growth. We thus identify a cascade of events downstream of genetic identity that direct posterior intestinal morphogenesis.

developmental biology↗

bioRxiv2023

Integrated Cell Landscape and Dynamics in the Progression of Bone Repair

Bone homeostasis and repair is a systematic progress with spatiotemporal interaction of multiple cell types involved in skeletal and immune system. Precise spatiotemporal regulation of cell type-specific functions in bone repair contributes to further development of tissue engineering and regenerative medicine. Here, we utilized single-cell RNA sequencing to illustrate a map of cell landscape and dynamics in the progression of rodent bone self-healing and a perturbation by lymphoid cell-deficiency. We identified different functions of myeloid cell and lymphoid cell to osteogenesis and angiogenesis during bone repair and their mutual complementation under lymphoid cell-deficient condition. Additionally, we used CD34+ humanized reconstituted mice to reveal further insights into the mechanism of human bone homeostasis and repair. Our integrated cellular analysis of bone repair explores the functional diversity and complementation between myeloid cells and lymphoid cells during bone healing process and provides further therapeutic implications for the treatment of bone disease and degeneration following ageing.

cell biology↗

bioRxiv2023

Plasma membrane association and resistosome formation of plant helper immune receptors

Intracellular plant immune receptors, termed NLRs, respond to pathogen effectors delivered into plant cells. Activation of NLRs typically confers immunity. Sensor NLRs, involved in effector recognition, are either TIR-NLRs (TNLs) or CC-NLRs (CNLs). Helper NLRs, required for sensor NLR signaling, include CCR-NLRs (RNLs) and a special class of CNLs known as NRCs. Activated TNLs produce small molecules that induce an association between the EDS1/SAG101 heterodimer and the NRG1s helper RNLs. Auto active NRG1s oligomerize and form calcium signaling channels largely localized at the plasma membrane (PM). The molecular mechanisms of helper NLR PM association and effector induced NRG1 oligomerization are not well characterized. We find that both RNLs and NRCs require positively charged residues in the second and fourth helices of their CCR or CC domain for phospholipid binding and PM association before and after activation, despite conformational changes that accompany activation. We demonstrate that effector activation of TNLs induces NRG1 oligomerization at the PM and that the cytoplasmic pool of EDS1/SAG101 is critical for cell death function. EDS1/SAG101 cannot be detected in the oligomerized NRG1 resistosome, suggesting that additional unknown triggers might be required to induce the dissociation of EDS1/SAG101 from the previously described NRG1/EDS1/SAG101 heterotrimer before subsequent NRG1 oligomerization, or that the conformational changes resulting from NRG1 oligomerization abrogate the interface for EDS1/SAG101 association. Our data provide new observations regarding dynamic PM association during helper NLR activation and underpin an updated model for effector induced NRG1 resistosome formation.

plant biology↗

bioRxiv2023

Acetylated dietary protein contributes to the acetylome in cells via KARS-mediated intra-translational deposition of acetyl-lysine in nascent protein

N6-acetyl-L-lysine residue is abundant in dietary protein but less is known about its potential influences on the diet-consumers. We herein report that KARS mediates intra- translational deposition of diet-derived N6-acetyl-L-lysine in nascent proteins to contribute the acetylome in cells. Acetylated dietary protein is a direct source of N6-acetyl-L-lysine that can widely and substantially contribute the acetylome in multiple organs of mice. By analyzing the co-crystal structure of Lysyl-tRNA synthetase (KARS) in complex with N6- acetyl-L-lysyl-AMP and pyrophosphate, together with in vitro biochemical assays, we learned that KARS can utilize N6-acetyl-L-lysine to produce N6-acetyl-L-lysyl-AMP and transfers the N6-acetyl-L-lysyl-moiety to lysine cognate tRNA to generate N6-acetyl-L- lysyl-tRNA, which introduces N6-acetyl-L-lysine into growing nascent polypeptide and intra-translationally results in protein acetylation. This undocumented protein modification mechanism is inherently different from post-translational modification (PTM) and termed as intra-translational modification (ITM). ITM can functionally mimic PTM mechanisms to deposit acetylation in histones to decondense chromatin. It can also modify PTM- inaccessible regions that are buried inside and functionally important to proteins. ITM is expected to extend the repertoire of acetylome and improve our understandings in protein modification modes in cells.

biochemistry↗

bioRxiv2022

Structure-Kinetic Relationship for Drug Design Revealed by PLS Model with Retrosynthesis-Based Pre-trained Molecular Representation and Molecular Dynamics Simulation

Drug design based on their molecular kinetic properties is growing in application. Pre-trained molecular representation based on retrosynthesis prediction model (PMRRP) was trained from 501 inhibitors of 55 proteins and successfully predicted the koff values of 38 inhibitors for HSP90 protein from an independent dataset. Our PMRRP molecular representation outperforms others such as GEM, MPG, and common molecular descriptors from RDKit. Furthermore, we optimized the accelerated molecular dynamics to calculate relative retention times for 128 inhibitors of HSP90. We observed high correlation between the simulated, predicted, and experimental -log(koff) scores. Combining machine learning (ML) and molecular dynamics (MD) simulation help design a drug with specific selectivity to the target of interest. Protein-ligand interaction fingerprints (IFPs) derived from accelerated MD further expedite the design of new drugs with the desired kinetic properties. To further validate our koff ML model, from the set of potential HSP90 inhibitors obtained by similarity search of commercial databases, we identified two novel molecules with better predicted koff values and longer simulated retention time than the reference molecules. The IFPs of the novel molecules with the newly discovered interacting residues along the dissociation pathways of HSP90 shed light on the nature of the selectivity of HSP90 protein. We believe the ML model described here is transferable to predict koff of other proteins and enhance the kinetics-based drug design endeavor.

biophysics↗

bioRxiv2022

The Genome of the Wasp Anastatus disparis Reveals Energy Metabolism Adaptations for Extreme Aggression.

Extremely aggressive behavior is rare in most species, as contestants can be severely injured or killed. Such high level of aggression can evolve when critical resources are limited, as the benefits of winning outweigh the potential costs of conflict. Currently, studies of extreme aggression are mainly from the perspectives of behavioral ecology and evolutionary biology, displaying distinct results from common nonextreme aggression. Here, we provide a high-quality genome of the generalist endoparasitoid Anastatus disparis, the males of which exhibit extreme mate-competition aggression, to shed light on possible genomic adaptations for extreme aggressive behavior. We combined Nanopore PromethION sequencing with Hi-C technology to assemble a high-quality chromosome-level genome of A. disparis. The size of the genome of this species (939.58 Mb) is larger than that of most hymenopterans (ranging from 180 Mb to 340 Mb) due to the expansion of repeated sequences (612.90 Mb, 65.23% of the whole genome). With the aid of RNA sequencing, 19,246 protein-coding genes were identified, and a great expansion of genes involved in detoxification was detected, which could represent an adaptation of this species to exploit a diverse range of known hosts. The integrated multiomics analysis highlighted genes involved in energy metabolism (especially from lipids) and antibacterial activity, both of which are possibly major aspects of adaptation for extreme aggression in A. disparis. Our study provides insight into molecular and evolutionary studies of extreme aggression in A. disparis and provides a valuable genomic resource for further research into the molecular basis of trait evolution in Hymenoptera.

genomics↗

bioRxiv2022

Whole-genome sequencing and single acute toxicity of heavy metal to Photobacterium kishitanii FJ21

In this study, the growth morphology of FJ21 strain was observed, and its 16S rRNA and whole genome were sequenced. Then, related software was used to make genome assembly, gene structure and function annotation, genome phylogenetic tree analysis, genome collinearity analysis and prediction of secondary metabolic gene cluster analysis. Finally, the single acute toxicity of five heavy metals to FJ21 strain was detected. There were luxC, luxD, luxA, luxB, luxF, luxE and luxG genes in FJ21, and the protein encoded by lux operon had certain hydrophilicity. The genome of this strain FJ21 contains a chromosome with a total length of 4853277bp and a GC content of 39.23%. The genome of FJ21 was compared with that of Photobacterium kishitanii ATCCBAA-1194, Photobacterium phosphoreum JCM21184, Photobacterium aquimaris LC2-065, Photobacterium malacitanum CECT9190, and Photobacterium carnosum TMW 2.2021. The average nucleotide identity(ANI), tetra nucleotide signatures (Tetra), comparative genome, and phylogenetic analysis proposed that FJ21 is a strain of Photobacterium kishitanii. In the acute toxicity test, the toxicity of heavy metals to the strain FJ21 is Pb(NO3)2 > ZnSO4{middle dot}7H2O > CdCl2{middle dot}2.5H2O > CuSO4{middle dot}5H2O > K2Cr2O7.

genomics↗

bioRxiv2022

Strong and consistent associations of waterbird community composition with HPAI H5 occurrence in European wild birds

Since 2014, highly pathogenic avian influenza (HPAI) H5 viruses of clade 2.3.4.4 have been dominating the outbreaks across Europe, causing massive deaths among poultry and wild birds. However, the factors shaping its broad-scale outbreak patterns remain unclear. With extensive waterbird survey datasets of about 7,000 sites across Europe, we here demonstrated that H5N8 occurrence in wild birds in the 2016/17 and 2020/21 epidemics as well as H5N1 occurrence in 2005/06 epidemic were strongly associated with very similar waterbird community attributes, pointing to the possibility of similar interspecific transmission processes between different epidemics. A simple extrapolation of the model constructed from the 2016/17 epidemic can well predict the H5N8 pattern in wild birds in 2020/21 epidemic. We also found a dilution effect of phylogenetic diversity that was always negatively correlated with H5 occurrence in wild birds. In contrast, H5N8 occurrence in poultry was subject to different risk factors between the two epidemics. In general, waterbird community composition play a much more important role in determining the spatial pattern of H5N8 in wild birds than in poultry. Our work contributes to reveal the factors driving H5N8 patterns, and highlights the value of waterbird community factors in future HPAI surveillance and prediction.

ecology↗

bioRxiv2022

Chemokine Receptor 1 and its associated immune pathway are downregulated in SF3B1MT blood and non-blood cancers

Mutation of the essential splicing factor SF3B1 is primarily associated with hematological cancers but also occurs in solid tumors. We edited the most common mutation, K700E, into human embryonic stem (ES) cells to determine the effects of this mutation alone in an undifferentiated/non-cancer background. Unexpectedly, >20% of the significantly upregulated genes in the SF3B1K700E ES lines have immune functions. Thus, SF3B1 may have an additional role in proper expression of immune genes in appropriate cell types. In striking contrast, we found that published RNA-seq data from SF3B1 blood (MDS, CLL, AML) and non-blood (BRCA, UVM) cancers exhibited the opposite, downregulation of a multitude of immune pathways with 7 of the pathways shared among all 5 of the SF3B1 cancers. One of these pathways, "leukocyte migration", is the 1st reported pathway shared among all splicing factor cancers, including the 5 SF3B1 cancers and MDS associated with U2AF1, SRSF2 and ZRSR2. Importantly, we identified CCR1, which is in the leukocyte migration pathway as the only shared downregulated gene in the 5 SF3B1 cancers and in U2AF1MT MDS. We conclude that downregulation of CCR1 and its associated immune pathway may play a key role in pathogenesis of these splicing factor cancers and are thus potential therapeutic targets.

molecular biology↗

bioRxiv2022

Identification of protein aggregates in the aging vertebrate brain with prion-like andphase separation properties

Protein aggregation, which can sometimes spread in a prion-like manner, is a hallmark of neurodegenerative diseases. However, whether prion-like aggregates form during normal brain aging remains unknown. Here we use quantitative proteomics in the African turquoise killifish to identify protein aggregates that accumulate in old vertebrate brains. These aggregates are enriched for prion-like RNA binding proteins, notably the ATP-dependent RNA helicase DDX5. We validate that DDX5 forms mislocalized cytoplasmic aggregates in the brains of old killifish and mice. Interestingly, DDX5s prion-like domain allows these aggregates to propagate across many generations in yeast. In vitro, DDX5 phase separates into condensates. Mutations that abolish DDX5 prion propagation also impair the proteins ability to phase separate. DDX5 condensates exhibit enhanced enzymatic activity, but they can mature into inactive, solid aggregates. Our findings suggest that protein aggregates with prion-like properties form during normal brain aging, which could have implications for the age-dependency of cognitive decline.

neuroscience↗