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bioRxiv2018

Genome-encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death

Innate immune signaling activation and DNA damage are pathological hallmarks of aging that may herald multiple adult-onset neurodegenerative diseases. Here, we report that both cell autonomous and non-autonomous neuronal death are triggered by the production of cytoplasmic double-stranded RNA (cdsRNA) from a regulated, disarticulated transgene in the setting of type I interferon (IFN-I) signaling. CdsRNA is a pathogen associated molecular pattern that induces IFN-I in many cell types. Transfection of a dsRNA mimetic into cultured human neurons also induces IFN-I signaling and cell death in a dose-dependent manner. Direct relevance to human disease is found in neurons of ALS-FTD patients carrying C9ORF72 intronic hexanucleotide expansions; cdsRNA isolated from these tissues is comprised of repeat sequences. Together, these findings implicate cdsRNA generated from genomic sequences in neurons as a trigger for sterile, viral-mimetic IFN-I induction and propagated neuronal death within in a neural circuit in the aging nervous system.

neuroscience↗

bioRxiv2018

Substrate deformations induce directed keratinocyte migration

Cell migration is an essential part of many (patho)physiological processes in the body, including keratinocyte re-epithelialization of healing wounds. Recent interest in the mechanobiology of tissues suggests that physical forces and mechanical cues from the wound bed (in addition to biochemical signals) may also play an important role in the healing process. Previously, we explored this possibility and found that polyacrylamide (PA) gel stiffness affected primary human keratinocyte behavior and that mechanical deformations in soft (~1.2 kPA) PA gels produced by neighboring cells appeared to influence the process of de novo epithelial sheet formation. In order to clearly demonstrate that keratinocytes do respond to such deformations, we conducted a series of experiments where we observed the response of single keratinocytes to a prescribed local substrate deformation that mimicked a neighboring cell or evolving multicellular aggregate via a servo-controlled microneedle. We also examined the effect of adding either Y27632, a rho kinase inhibitor, or blebbistatin, a non-muscle myosin II inhibitor, on the response of the cells to PA gel deformations. The results of this study indicate that keratinocytes do sense and respond to mechanical signals comparable to those that originate from substrate displacements imposed by neighboring cells, a finding that could have important implications for the process of keratinocyte re-epithelialization that takes place during normal and pathologic wound healing. Furthermore, the Rho/ROCK pathway and the engagement of NM II are both essential to the observed process of substrate deformation-directed keratinocyte migration.

biophysics↗

bioRxiv2018

Electrical Excitability of the Endoplasmic Reticulum Membrane Drives Electrical Bursting and the Pulsatile Secretion of Insulin in a Pancreatic Beta Cell Model

Pancreatic {beta}-cells secrete insulin, the hormone that controls glucose homeostasis in vertebrates. When activated by glucose, {beta}-cells display a biphasic electrical response. An initial phase, in which the cell fires action potentials continuously, is followed by a phase with a characteristic firing pattern, known as electrical bursting, that consists on brief pulses of action potentials separated by intervals of rest. Electrical bursting is believed to mediate the pulsatile secretion of insulin. The electrical response of {beta}-cells has been extensively studied at experimental and theoretical level. However, there is still no consensus on the cellular mechanisms that underlie each of the phases of the response. In this paper, I propose the hypothesis that the pattern of the plasma membrane (PM) response of stimulated {beta}-cells is generated by the electrical activity of the endoplasmic reticulum (ER) membrane. In this hypothesis, the interaction of the two excitable membranes, PM and ER membrane, each operating at a different time scale, generates both, the initial continuous phase and the periodic bursting phase. A mathematical model based on the hypothesis is presented. The behavior of the model {beta}-cell replicates the main features of the physiological response of pancreatic {beta}-cells to nutrients and to neuro-endocrine regulatory factors. The model cell displays a biphasic response to the simulated elevation of glucose. It generates electrical bursting with frequencies comparable to those observed in live cells. The simulation of the action of regulatory factors mimics the actual effect of the factors on the frequency of bursting. Finally, the model shows that a cell with a defective ER response behaves like a dysfunctional {beta}-cell from individuals with type 2 diabetes mellitus, a result that suggests that the electrical malfunction of the ER membrane may represent one of the primary causes of type 2 diabetes. Dynamic analysis of the ER behavior has revealed that, depending on the transport rates of Ca2+ in and out of the ER, the system has three possible dynamic states. They consist on the hyperpolarization of the ER membrane, periodic oscillations of the electric potential across the membrane, and the depolarization of the membrane. Each of these states determines a different functional program in the cell. The hyperpolarized state maintains the cell at rest, in a non-secreting state. Periodic oscillations of the ER membrane cause electrical bursting in the PM and the consequent pulsatile secretion of insulin. Finally, the depolarized state causes continuous firing and an acute secretory activity, the hyperactive conditions of the initial phase of the {beta}-cell response to glucose. The dynamic states of the ER are also associated with different long-term effects. So, conditions that induce the hyperactive depolarized state in {beta}-cells also potentiate apoptosis. The induction of the oscillatory state by glucose and neuro-endocrine factors seems to activate also cell proliferation. In extreme conditions though, such as the chronic treatment of T2DM with incretin analogs, the activation of the oscillatory state may lead to the appearance of cancer. The mathematical model presented here is an illustration of how, even in a extremely simplified system, the nonlinearity or excitability of the ER membrane can produce a repertoire of dynamic states that are able to generate a complex response comparable to the response observed experimentally in pancreatic {beta}-cells. In actual cells, with a much higher number of parameters susceptible to be modified by environmental and genetic factors, the ER membrane is likely to have a significantly bigger set of dynamic states each capable to direct the cell in a particular functional or developmental direction. The potential role of the electrical activity of the ER membrane in cellular processes such as fertilization, cell proliferation and differentiation, and cell death, as well as in the development of diverse pathological conditions is analyzed in the discussion.

cell biology↗

bioRxiv2018

Using normative age modelling to isolate subsets of individuals with autism expressing highly age-atypical cortical thickness features

Understanding heterogeneity in neural phenotypes is an important goal on the path to precision medicine for autism spectrum disorders (ASD). Age is a critically important variable in normal structural brain development and examining structural features with respect to age-related norms could help to explain ASD heterogeneity in neural phenotypes. Here we examined how cortical thickness (CT) in ASD can be parameterized as an individualized metric of deviance relative to typically-developing (TD) age-related norms. Across a large sample (n=870 per group) and wide age range (5-40 years), we applied a normative modelling approach that provides individualized whole-brain maps of age-related CT deviance in ASD. This approach isolates a subgroup of ASD individuals with highly age-deviant CT. The median prevalence of this ASD subgroup across all brain regions is 7.6%, and can reach as high as 10% for some brain regions. This work showcases an individualized approach for understanding ASD heterogeneity that could potentially further prioritize work on a subset of individuals with significant cortical pathophysiology represented in age-related CT deviance. Rather than cortical thickness pathology being a widespread characteristic of most ASD patients, only a small subset of ASD individuals are actually highly deviant relative to age-norms. These individuals drive small on-average effects from case-control comparisons. Rather than sticking to the diagnostic label of autism, future research should pivot to focus on isolating subsets of autism patients with highly deviant phenotypes and better understand the underlying mechanisms that drive those phenotypes.

neuroscience↗

bioRxiv2018

A genetically encoded biosensor reveals location bias of opioid drug action

Opioid receptors (ORs) precisely modulate behavior when activated by native peptide ligands but distort behaviors to produce pathology when activated by non-peptide drugs. A fundamental question is how drugs differ from peptides in their actions on target neurons. One way that drugs can differ is by imposing selective effects on the conformational equilibrium of individual ORs. We wondered if drugs can also impose selective effects on the location of OR activation in individual OR-expressing neurons. Here we develop a genetically encoded biosensor that directly localizes ligand-induced activation and deactivation of ORs in living cells, and use it to generate the first real-time map of the spatiotemporal organization of - and {delta}-OR activation in neurons. Peptide agonists produce a characteristic activation pattern initiated in the plasma membrane and propagating to endosomes after receptor internalization. Drugs produce a different activation pattern by uniquely driving OR activation in the somatic Golgi apparatus and extending throughout the dendritic arbor in Golgi outposts. These results demonstrate a new approach to probe the cellular basis of neuromodulation and reveal that drugs profoundly distort the spatiotemporal landscape of neuronal OR activation.

neuroscience↗

bioRxiv2018

Sub-voxel light-sheet microscopy for high-resolution, high-throughput volumetric imaging of large biomedical specimens

A key challenge when imaging whole biomedical specimens is how to quickly obtain massive cellular information over a large field of view (FOV). Here, we report a sub-voxel light-sheet microscopy (SLSM) method enabling high-throughput volumetric imaging of mesoscale specimens at cellular-resolution. A non-axial, continuous scanning strategy is used to rapidly acquire a stack of large-FOV images with three-dimensional (3-D) nanoscale shifts encoded. Then by adopting a sub-voxel-resolving procedure, the SLSM method models these low-resolution, cross-correlated images in the spatial domain and iteratively recovers a 3-D image with improved resolution throughout the sample. This technique can surpass the optical limit of a conventional light-sheet microscope by more than three times, with high acquisition speeds of gigavoxels per minute. As demonstrated by quick reconstruction (minutes to hours) of various samples, e.g., 3-D cultured cells, an intact mouse heart, mouse brain, and live zebrafish embryo, the SLSM method presents a high-throughput way to circumvent the tradeoff between intoto mapping of large-scale tissue (>100 mm3) and isotropic imaging of single-cell (~1-m resolution). It also eliminates the need of complicated mechanical stitching or precisely modulated illumination, using a simple light-sheet setup and fast graphics-processing-unit (GPU)-based computation to achieve high-throughput, high-resolution 3-D microscopy, which could be tailored for a wide range of biomedical applications in pathology, histology, neuroscience, etc.

bioengineering↗

bioRxiv2018

Tetracyclines Modify Translation By Targeting Key Human rRNA Substructures.

Apart from their antimicrobial properties, tetracyclines demonstrate clinically validated effects in the amelioration of pathological inflammation and human cancer. Delineation of the target(s) and mechanism(s) responsible for these effects, however, has remained elusive. Here, employing quantitative mass spectrometry-based proteomics, we identified human 80S ribosomes as targets of the tetracyclines Col-3 and doxycycline. We then developed in cell click selective crosslinking with RNA sequence profiling (icCL-Seq) to map binding sites for these tetracyclines on key human rRNA substructures at nucleotide resolution. Importantly, we found that structurally and phenotypically variant tetracycline analogs could chemically discriminate these rRNA binding sites. We also found that tetracyclines both subtly modify human ribosomal translation and selectively activate the cellular integrated stress response (ISR). Together, the data reveal that targeting of specific rRNA substructures, activation of the ISR, and inhibition of translation are correlated with the anti-proliferative properties of tetracyclines in human cancer cell lines.

cell biology↗

bioRxiv2018

On a Robust, Sensitive Cell-Free Method for Pseudomonas Sensing and Quantification

Cell - free lysates have found a utility in performing cellular functions and providing biologically-relevant metabolic products without the optimal biological conditions for growth and proliferation. By teasing out the biological components and constructing artificial conditions that enable for biological transcription and translation processes to occur, specific cell - like functions can be reconstituted in vitro without requiring the entire cell and milieu of cellular organelles. This enables for optimization of biological circuits, either by concentration or on/off switches, simply through the addition or removal of genetic components (plasmids, inducers, or repressors) of regulatory elements. Here, we demonstrate an application of cell - free process that is robust and portable, independent of a substrate, to apply for sensing and reporting functions of a quorum sensing molecule N-3-oxododecanoyl homoserine lactone (3OC12HSL) found crucial for pathological Pseudomonas infections. Using droplet microfluidics to integrate cell - free related functions into hydrogel scaffolds, we show that these cell - free circuits can be encapsulated, delivered, and activated in most environments--even in conditions with very little hydration.

synthetic biology↗

bioRxiv2018

Inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates seizures by enhancing A-type potassium currents

The heat shock protein 70 (Hsp70) is upregulated in response to stress and has been implicated as a stress marker in temporal lobe epilepsy (TLE). However, whether Hsp70 plays a pathologic or protective role in TLE remains unclear. Here we report that Hsp70 exerts an unexpected deleterious role in kainic acid (KA)-induced seizures, and inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates both acute and chronic seizures via enhancing A-type potassium currents primarily formed by Kv4 -subunits and auxiliary KChIPs. Proteosomal degradation of Kv4-KChIP4a channel complexes is enhanced by Hsp70, which can be reversed by the Hsp70 inhibitors, 2-phenylethynesulfonamide (PES) and VER-155008 (VER). In cultured hippocampal neurons, either PES or VER can increase A-type Kv4 current to suppress neuronal hyperexcitability. Mechanistically, Hsp70-CHIP complexes directly bind to the N-terminus of auxiliary KChIP4a and target Kv4-KChIP4a complexes to the proteasome. Our findings reveal a previously unrecognized role of Hsp70 in mediating degradation of Kv4-KChIP4a complexes and regulating neuronal excitability, thus highlighting a therapeutic potential for hyperexcitability-related neurological disorders through Hsp70 inhibition.

neuroscience↗

bioRxiv2018

MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways

MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here we describe a neuroprotective function of miR-132, the miRNA most significantly down-regulated in Alzheimers disease. miR-132 protects mouse and human wild-type neurons and more vulnerable Tau-mutant primary neurons against amyloid {beta}-peptide (A{beta}) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF Tau pathology and neurodegeneration and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3{beta}, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.

neuroscience↗

bioRxiv2018

Two parallel pathways implement robust propionate catabolism and detoxification in mycobacteria

Tuberculosis remains a major global health threat with over 1.5 million deaths each year. Mycobacterium tuberculosis success story is related to a flexible metabolism, allowing growth despite restrictive conditions within the human host.\n\nHost lipids stores are a major carbon source in vivo. Their catabolism yields propionyl-CoA, which is processed by two parallel pathways, the methylmalonyl CoA pathway and the methylcitrate pathway. Both pathways are considered potential drug targets. The methylcitrate pathway is upregulated in the pathological context. However, intermediates of this pathway can be cytotoxic and Mtbs preference for its usage remains unclear.\n\nWe combine thermodynamic kinetic modeling, quantitative proteomics and time-resolved metabolomics to characterize the interplay between the two pathways and to show their functionalities in an efficient and fast propionate catabolism.\n\nWe find that the methylcitrate pathway acts as a transcriptionally regulated, high capacity catabolic pathway due to its favorable thermodynamics and metabolic control distribution. In contrast, the methylmalonyl pathway is constitutively fulfilling biosynthetic tasks and can quickly detoxify propionate pulses, but is thermodynamically restricted to lower capacity.

systems biology↗

bioRxiv2018

Osteoclasts control sensory neurons axonal growth through epidermal growth factor receptor signaling

The patterning of peripheral innervation is accomplished through the tissue expression, in specific space and timeframe, of attractive or repulsive axonal guidance cues. At the bone microenvironment, neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, vascular endothelial growth factor, netrin-1 and others were described to regulate the nerve ingrowth towards the bone compartment, by acting directly on receptors expressed at the nerve terminals. Interestingly, besides the gradient of soluble factors, neurons were described to be responsive to extracellular vesicles (EV) derived from myelinating cells and mesenchymal stem cells. Here we provide evidence on a new mechanism by which peripheral innervation can be coordinated. We show that sensory nerves outgrowth and electric signal propagation are dependent on the EV secreted by osteoclasts, the bone resorbing cells. Furthermore, we demonstrate that the axonal sprouting is achieved through the activation of epidermal-growth factor receptor (EGFR) family signaling pathway. We proved that the EV-depleted osteoclast secretome leads to a significant decrease of neurons firing rate and axonal sprouting, concomitant with a decrease of EGFR/ErbB2 activation levels. Excitingly, the proteomic analysis of the osteoclast-derived EV cargo shows a high correlation with synaptic components reinforcing the role on sensory neurons/osteoclast crosstalk. Our findings that osteoclast-derived EV hold effect in axonal outgrowth, contributing actively to the dynamics of the sensory neurons sprouting and electrophysiology, is a step toward unraveling target mechanisms to control electrical signal propagation and nerve fibers sprouting and consequently open new avenues for the development of innovative therapies to control bone pain. Significance StatementSensory nerve fibers sprouting in bone pathologies is highly associated with pain. Thus, understanding the mechanisms behind sensory nerves ingrowth, sprouting and electrical activity, within the bone compartment, is essential for improving the strategies to overcome pain in bone disorders. We provide a new mechanism on the sensory nerves sprouting, indicating that the effect is dependent on the extracellular vesicles (EV) released by osteoclasts, through the epidermal growth factor receptor family targeting, by integrin independent pathways. We show different electrophysiology patterns being triggered in the presence of osteoclasts secretome and the abolishment of sensory neurons firing rate in EV-depleted conditions. Overall, our results elucidate novel mechanisms on the peripheral nerves sprouting, essential for pursuing new targets for bone pain therapies.

cell biology↗

bioRxiv2018

The role of Aβ circRNA in Alzheimer’s disease

Alzheimers disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (A{beta}) play a crucial role in the pathology of AD. In familial AD, A{beta} is generated from the full-length amyloid precursor protein (APP) via dysregulated proteolytic processing. However, A{beta} biogenesis in case of sporadic AD remains so far elusive. circRNAs are a class of transcripts, which are preferentially expressed in brain. Here, we identified a circRNA (circA{beta}-a) derived from the A{beta}-coding region of the APP gene. circA{beta}-a is expressed in brains of AD and nondementia controls. With the aid of our recently established approach for analysis of circRNA functions, we demonstrated that circA{beta}-a is efficiently translated into a novel A{beta}-related A{beta}175 protein in living cells. Importantly, A{beta}175 was further processed to A{beta} peptides, the hallmark of AD. In summary, our analysis revealed alternative route of A{beta} biogenesis. circA{beta}-a and its corresponding protein might represent novel therapeutic targets for AD treatment.

neuroscience↗

bioRxiv2018

psichomics: graphical application for alternative splicing quantification and analysis

Alternative pre-mRNA splicing generates functionally distinct transcripts from the same gene and is involved in the control of multiple cellular processes, with its dysregulation being associated with a variety of pathologies. The advent of next-generation sequencing has enabled global studies of alternative splicing in different physiological and disease contexts. However, current bioinformatics tools for alternative splicing analysis from RNA-seq data are not user-friendly, disregard available exon-exon junction quantification or have limited downstream analysis features. To overcome such limitations, we have developed psichomics, an R package with an intuitive graphical interface for alternative splicing quantification and downstream dimensionality reduction, differential splicing and gene expression and survival analyses based on The Cancer Genome Atlas, the Genotype-Tissue Expression project and user-provided data. These integrative analyses can also incorporate clinical and molecular sample-associated features. We successfully used psichomics to reveal alternative splicing signatures specific to stage I breast cancer and associated novel putative prognostic factors.

bioinformatics↗

bioRxiv2018

DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory organ of Corti

BackgroundThe mammalian inner ear is a complex morphological structure responsible for hearing and balance, and its pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics in the development and maturation of mouse inner ear sensory epithelium, we performed whole-genome bisulfite sequencing on inner ear tissue, yielding temporal base-pair resolution methylomes at key developmental time points.\n\nResultsWe found a late accumulation of non-CpG methylation, indicating a similarity between the inner ear sensory epithelium and neuronal tissue. Moreover, annotation of both unmethylated and low methylated regions pointed to regulatory elements active in the inner ear in proximity of and distal from transcriptional units. Finally, we identified differentially methylated regions across the transition periods. An analysis of these regions led us to identify several novel candidate regulatory factors, connecting regulatory elements from specific time points in development to molecular features that drive the development and maturation of the inner ear sensory epithelium. The GJB6 locus putative regulatory region was shown to upregulate distal GJB6 gene expression and a non-coding RNA.\n\nConclusionsOur analysis of inner ear sensory epithelium DNA methylation sheds light on novel regulatory regions in the hearing organ, and may help boost diagnostic capabilities and guide the development of therapeutics for hearing loss, by providing multiple intervention points for manipulation of the auditory system.

genomics↗

bioRxiv2018

Bacterial division FtsZ forms liquid condensates with nucleoid-associated Z-ring inhibitor SlmA

Macromolecular condensation resulting from biologically regulated liquid-liquid phase transitions is emerging as a mechanism to organize the intracellular space in eukaryotic systems, with broad implications in cell physiology and pathology. Here we show that FtsZ, central element of the division ring in most bacteria, forms condensates when in complex with SlmA, the protein preventing septal ring assembly nearby the chromosome in E. coli. The formation of condensates is promoted by crowding and enhanced by sequence-specific binding of SlmA to DNA. These structures are dynamic and FtsZ within them remains active for GTP-triggered fiber formation. Their location is sensitive to compartmentalization and to the presence of a membrane boundary in microfluidics-based cell mimetic systems, likely affecting their reactivity. We propose that reversible condensation may play a role in the modulation of FtsZ assembly and/or location by SlmA and, hence, in the regulation of ring stability, constituting a singular example of a prokaryotic nucleoprotein complex exhibiting this kind of phase transition.

biochemistry↗

bioRxiv2018

A widespread decrease of chromatin accessibility in age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. The extent to which epigenetic changes regulate AMD progression is unclear. Here we globally profiled chromatin accessibility in the retina and retinal pigmented epithelium (RPE) from AMD patients and controls. Global decreases in chromatin accessibility occurr in RPE in early AMD, and in the retina with advanced disease, suggesting that dysfunction in RPE cells drives disease progression. Footprints of photoreceptor and RPE-specific transcription factors are enriched in differentially accessible regions (DARs). Genes associated with DARs show altered expression in AMD. Cigarette smoke treatment of RPE cells recapitulates epigenomic changes seen in AMD, providing an epigenetic link between the known risk factors for AMD and AMD pathology. Finally, overexpression of HDAC11 is partially responsible for the reduction in chromatin accessibility, identifying potential new targets for treatment of AMD.

genomics↗

bioRxiv2018

PET by MRI: Glucose Imaging by 13C-MRS without Dynamic Nuclear Polarization by Noise Suppression through Tensor Decomposition Rank Reduction

Metabolic reprogramming is one of the defining features of cancer and abnormal metabolism is associated with many other pathologies. Molecular imaging techniques capable of detecting such changes have become essential for cancer diagnosis, treatment planning, and surveillance. In particular, 18F-FDG (fluorodeoxyglucose) PET has emerged as an essential imaging modality for cancer because of its unique ability to detect a disturbed molecular pathway through measurements of glucose uptake. However, FDG-PET has limitations that restrict its usefulness in certain situations and the information gained is limited to glucose uptake only. 13C magnetic resonance spectroscopy theoretically has certain advantages over FDG-PET, but its inherent low sensitivity has restricted its use mostly to single voxel measurements. We show here a new method of imaging glucose metabolism in vivo that relies on a simple, but robust and efficient, post-processing procedure by the higher dimensional analog of singular value decomposition, tensor decomposition. Using this procedure, we achieve an order of magnitude increase in signal to noise in both dDNP and non-hyperpolarized non-localized experiments without sacrificing accuracy. In CSI experiments an approximately 30-fold increase was observed, enough that the glucose to lactate conversion indicative of the Warburg effect can be imaged without hyper-polarization with a time resolution of 12 s and an overall spatial resolution that compares favorably to 18F-FDG PET.

cancer biology↗