Biology subjects

Kim, H.-J.

Publications and source records attributed to Kim, H.-J..

44 records · Page 3Linked to original sources

bioRxiv2019

C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent accumulation of Staufen in nucleus

Accumulation of RNA in the nucleus is one of the pathological features of C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), yet its potential toxic cellular consequences remain largely undefined. RNA accumulated in the nucleus may interact with and increase nuclear localization of RNA-binding proteins (RBPs). Here, we show in C9-ALS/FTD Drosophila melanogaster model that Staufen, a double-stranded RBP normally localized in cytoplasm, accumulates in the nucleus, which is in contrast to many nuclear-localized RBPs, such as TDP-43 and FUS, whose cytoplasmic accumulation is thought to be a pathological hallmark of ALS/FTD. We found that in Drosophila neurons expressing arginine-rich dipeptide repeat proteins (DPRs), Staufen accumulated in the nucleus in an RNA-dependent manner. In the nucleus, Staufen localized closely to, and potentially interacts with, heterochromatin and nucleolus in Drosophila C4 da neurons expressing poly(PR), a proline-arginine (PR) DPR. PR toxicity in C4 da neurons increased Fibrillarin staining in the nucleolus, which was enhanced by stau heterozygous mutation. Furthermore, knockdown of fib exacerbated retinal degeneration mediated by PR toxicity, which suggests that increased amount of Fibrillarin by stau heterozygous mutation is protective. Heterozygotic mutation of stau could also mitigate retinal degeneration and rescue viability of flies exhibiting PR toxicity. Taken together, our data show that nuclear accumulation of cytoplasmic protein, such as Staufen, may also be an important pathological feature of C9-ALS/FTD.\n\nAuthor summaryCytoplasmic accumulation of nuclear RNA-binding proteins (RBPs) is one of the common pathological features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In C9orf72-associated ALS/FTD fly model, we found that Staufen, a double-stranded (ds) RBP normally localized mostly in cytoplasm, accumulates in the nucleus in an RNA-dependent manner. Next, we checked wherein the nucleus Staufen accumulates and found that Staufen partially co-localizes with heterochromatin and nucleolus. Interestingly, the expression of Fibrillarin, a nucleolar protein, was significantly increased by C9orf72-derived PR toxicity and further augmented by reduction in stau dosage, the gene encoding Staufen. When we knocked down fib, the gene encoding Fibrillarin, PR-induced retinal degeneration was exacerbated. This indicates that increased Fibrillarin expression by stau dosage reduction is protective. Furthermore, when we reduced stau dosage in flies presenting PR toxicity, their retinal degeneration and viability were largely rescued. Based on these data, we suggest that nuclear accumulation of Staufen is an important feature of C9-ALS/FTD and suggest that reducing stau dosage is a promising therapeutic target.

genetics↗

bioRxiv2019

Dynamic healing and remodeling of mandibular ramus in segmental mobility and cortical overlap after intraoral vertical osteotomy

The ramus immediately after intraoral vertical ramus osteotomy (IVRO) shows segmental mobility, cortical overlap, and projection, which yield smooth-surfaced continuity and stability after one year. This study aimed to elucidate the three-dimensional (3D) morphological changes driven by regional healing and remodeling 12 months postoperatively (Post) and their relationships with the immediate postoperative (Imm) segmental overlapping pattern. We performed a retrospective study of the morphological change of mandibular ramus in terms of time and amount of cortical overlap after IVRO. 3D computed tomography data of 108 hemi-mandibles were analyzed by independent superimposition of Imm proximal and distal segment to Post mandible. Analysis showed extensive regional bone resorption and apposition resulting in a relatively flat-surfaced and morphologically intact Post ramus. The middle ramal remodeling was significantly associated with Imm overlapping patterns and Post mandibular movement, new bony projections of various shapes being observed at the posterior border of the Post ramus. The ramus after IVRO underwent dynamic morphological changes during healing/remodeling which were partly associated with Imm overlap. Moreover, the Post functional and smooth-surfaced ramus seems to have been facilitated by the close surgical approximation of segments and the postoperative mandibular functional rehabilitation, even with segmental positional changes.

pathology↗

bioRxiv2019

Raptor genomes reveal evolutionary signatures of predatory and nocturnal lifestyles

BackgroundBirds of prey (raptors) are dominant apex predators in terrestrial communities, with hawks (Accipitriformes) and falcons (Falconiformes) hunting by day, and owls (Strigiformes) hunting by night.\n\nResultsHere, we report new genomes and transcriptomes for 20 species of birds, including 16 species of birds of prey, and high-quality reference genomes for the Eurasian eagle-owl (Bubo bubo), oriental scops-owl (Otus sunia), eastern buzzard (Buteo japonicus), and common kestrel (Falco tinnunculus). Our extensive genomic analysis and comparisons with non-raptor genomes identified common molecular signatures that underpin anatomical structure and sensory, muscle, circulatory, and respiratory systems related to a predatory lifestyle. Compared with diurnal birds, owls exhibit striking adaptations to the nocturnal environment, including functional trade-offs in the sensory systems (e.g., loss of color vision genes and selection for enhancement of nocturnal vision and other sensory systems) that are probably convergent with other nocturnal avian orders. Additionally, we found that a suite of genes associated with vision and circadian rhythm were differentially expressed between nocturnal and diurnal raptors, indicating adaptive expression change during the transition to nocturnality.\n\nConclusionsOverall, raptor genomes showed genomic signatures associated with the origin and maintenance of several specialized physiological and morphological features essential to be apex predators.

genomics↗

bioRxiv2019

Capturing cell type-specific chromatin structural patterns by applying topic modeling to single-cell Hi-C data

Single-cell Hi-C (scHi-C) interrogates genome-wide chromatin interaction in individual cells, allowing us to gain insights into 3D genome organization. However, the extremely sparse nature of scHi-C data poses a significant barrier to analysis, limiting our ability to tease out hidden biological information. In this work, we approach this problem by applying topic modeling to scHi-C data. Topic modeling is well-suited for discovering latent topics in a collection of discrete data. For our analysis, we generate twelve different single-cell combinatorial indexed Hi-C (sciHi-C) libraries from five human cell lines (GM12878, H1Esc, HFF, IMR90, and HAP1), consisting over 25,000 cells. We demonstrate that topic modeling is able to successfully capture cell type differences from sciHi-C data in the form of "chromatin topics." We further show enrichment of particular compartment structures associated with locus pairs in these topics.

genomics↗

bioRxiv2018

Oligomeric α-synuclein-specific degradation by HtrA2/Omi to bestow a neuroprotective function

Although the malfunction of HtrA2/Omi leads to Parkinsons disease (PD), the underlying mechanism has remained unknown. Here, we showed that HtrA2/Omi specifically removed oligomeric -Syn but not monomeric -Syn to protect oligomeric -Syn-induced neurodegeneration. Experiments using mnd2 mice indicated that HtrA2/Omi degraded oligomeric -Syn specifically without affecting monomers. Transgenic Drosophila melanogaster experiments of the co-expression -Syn and HtrA2/Omi and expression of genes individually also confirmed that pan-neuronal expression of HtrA2/Omi completely rescued Parkinsonism in the -Syn-induced PD Drosophila model by specifically removing oligomeric -Syn. HtrA2/Omi maintained the health and integrity of the brain and extended the life span of transgenic flies. Because HtrA2/Omi specifically degraded oligomeric -Syn, co-expression of HtrA2/Omi and -Syn in Drosophila eye maintained a healthy retina, while the expression of -Syn induced retinal degeneration. This work showed that the bacterial function of HtrA to degrade toxic misfolded proteins is evolutionarily conserved in mammalian brains as HtrA2/Omi.

neuroscience↗

bioRxiv2018

A conserved morphogenetic mechanism for epidermal ensheathment of nociceptive sensory neurites

Interactions between epithelial cells and neurons influence a range of sensory modalities including taste, touch, and smell. Vertebrate and invertebrate keratinocytes/keratinocyte-like epidermal cells ensheath peripheral arbors of somatosensory neurons, including nociceptors, yet the developmental origins and functional roles of this ensheathment are largely unknown. Here, we describe an evolutionarily conserved morphogenetic mechanism for epidermal ensheathment of somatosensory neurites. We found that somatosensory neurons in Drosophila and zebrafish induce formation of epidermal sheaths, which wrap neurites of different types of neurons to different extents. Neurites induce formation of plasma membrane phosphatidylinositol 4,5-bisphosphate microdomains at nascent sheaths, followed by a filamentous actin network, and recruitment of junctional proteins that likely form autotypic junctions to seal sheaths. Finally, blocking epidermal sheath formation destabilized dendrite branches and reduced nociceptive sensitivity in Drosophila. Epidermal somatosensory neurite ensheathment is thus a deeply conserved cellular process that contributes to the morphogenesis and function of nociceptive sensory neurons.

neuroscience↗

bioRxiv2018

PTK2 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathy

TDP-43 proteinopathy is a common feature in a variety of neurodegenerative disorders including Amyotrophic lateral sclerosis (ALS) cases, Frontotemporal lobar degeneration (FTLD), and Alzheimers disease. However, the molecular mechanisms underlying TDP-43-induced neurotoxicity are largely unknown. In this study, we demonstrated that TDP-43 proteinopathy induces impairment in ubiquitin-proteasome system (UPS) evidenced by an accumulation of ubiquitinated proteins and reduction of proteasome activity in neuronal cells. Through kinase inhibitor screening, we identified PTK2 as a suppressor of neurotoxicity induced by UPS impairment. Importantly, PTK2 inhibition significantly reduces ubiquitin aggregates and attenuated TDP-43-induced cytotoxicity in Drosophila model of TDP-43 proteinopathy. We further identified that phosphorylation of p62 at serine 403 (p-p62S403), a key component in the autophagic degradation of poly-ubiquitinated proteins, is increased upon TDP-43 overexpression and dependent on activation of PTK2 in neuronal cells. Moreover, expressing a non-phosphorylated form of p62 (p62S403A) significantly represses accumulation of polyubiquitinated proteins and neurotoxicity induced by TDP-43 overexpression in neuronal cells. In addition, inhibition of TBK1, a kinase which phosphorylates S403 of p62, ameliorates neurotoxicity upon UPS impairment in neuronal cells. Taken together, our data suggest that activation of PTK2-TBK1-p62 axis plays a critical role in the pathogenesis of TDP-43 by regulating neurotoxicity induced by UPS impairment. Therefore, targeting PTK2-TBK1-p62 axis may represent a novel therapeutic intervention for neurodegenerative diseases with TDP-43 proteinopathy.

neuroscience↗

bioRxiv2018

Vascular defects of DYRK1A knockouts are ameliorated by modulating calcium signaling in zebrafish

DYRK1A is a major causative gene in Down syndrome (DS). Reduced incidence of solid tumors and vascular anomalies in DS patients suggests a role of DYRK1A in angiogenesis, but in vivo evidence is lacking. Here, we used zebrafish dyrk1aa mutant embryos to understand DYRK1A function in the cerebral vasculature formation. Zebrafish dyrk1aa mutants exhibited cerebral hemorrhage and defects in angiogenesis of central arteries in the developing hindbrain. Such phenotypes were rescued by wild-type dyrk1aa mRNA, but not by a kinase-dead form, indicating the importance of DYRK1A kinase activity. Chemical screening using a bioactive small molecule library identified a calcium chelator, EGTA, as one of the hits that most robustly rescued the hemorrhage. Vascular defects of mutants were also rescued by independent modulation of calcium signaling by FK506. Furthermore, the transcriptomic analyses supported the alterations of calcium signaling networks in dyrk1aa mutants. Together, our results suggest that dyrk1aa plays an essential role in angiogenesis and in maintenance of the developing cerebral vasculature via regulation of calcium signaling, which may have therapeutic potential for DYRK1A-related vascular diseases.

developmental biology↗