k-shell decomposition reveals structural properties of the gene coexpression network for neurodevelopment

Neurodevelopment is a dynamic and complex process, which involves interactions of thousands of genes. Understanding the mechanisms of brain development is important for uncovering the genetic architectures of neurodevelopmental disorders such as autism spectrum disorder and intellectual disability. The BrainSpan dataset is an important resource for studying the transcriptional mechanisms governing neurodevelopment. It contains RNA-seq and microarray data for 13 developmental periods in 8-16 brain regions. Various important studies used this dataset, in particular to generate gene coexpression networks. The topology of the BrainSpan gene coexpression network yielded various important gene clusters, which are found to play key roles in diseases. In this work, we analyze the topology of the BrainSpan gene coexpression network using the k-shell decomposition method. k-Shell decomposition is an unsupervised method to decompose a network into layers (shells) using the connectivity information and to detect a nucleus that is central to overall connectivity. Our results show that there are 267 layers in the BrainSpan gene coexpression network. The nucleus contains 2584 genes, which are related to chromatin modification function. We compared and contrasted the structure with the autonomous system level Internet. We found that despite similarities in percolation transition and crust size distribution, there are also differences: the BrainSpan coexpression network has a significantly large nucleus and only a very small number of genes need to access the nucleus first, to be able to connect to other genes in the crust above the nucleus. © TÜBİTAK

Cytoplasmic protein aggregates interfere with nucleo-cytoplasmic transport of protein and RNA

Protein misfolding and aggregation are linked to various forms of dementia and amyloidoses, such as Alzheimer’s, Parkinson’s, and Creutzfeldt Jakob diseases. Although the primary misfolding proteins are disease-specific and structurally diverse, the related disorders share numerous symptoms and cellular malfunctions. A sustainable cure remains so far out of reach. The highly complex nature of the associated cellular deficiencies challenges our understanding of primary causes and consequences in the disease progression. To focus on the toxic properties and pathogenic gain-of-function mechanisms of misfolded structures in cells, we applied a set of artificial β proteins directly folding into amyloid-like oligomers and fibrils. Amyloid-related proteotoxicity appeared sequence-dependently in human, murine neuronal, fungal, and bacterial cells. The interplay between elevated surface hydrophobicity and structural disorder among the β proteins and their cellular interactors was critical for toxicity. Small distributed oligomers correlated to elevated toxicity. Protein-rich plaques or misfolded assemblies appear in patients often simultaneously in different cellular compartments and in the extracellular space. To analyze site-specific toxicities and vulnerabilities, we targeted the β proteins specifically into distinct compartments. Aggregation in the cytoplasm was highly toxic and interfered with active nucleo-cytoplamsic transport in both directions, including the translocation of NF-κB and mRNA. We compared our results to human disease-associated mutants of Huntingtin, TDP-43, and Parkin, causing comparable transport defects. Remarkably, toxicity of the β proteins was strongly reduced when targeted to the nucleus. Aggregates localized in dense nucleolar foci caused no transport inhibition. Only protein aggregation in the cytoplasm led to sequestration and mislocalization of numerous proteins with extended disordered regions, including factors involved in nucleo-cytoplasmic transport of proteins and mRNA (importin α and THOC proteins). Nuclear β proteins in contrast behaved very inert, potentially being shielded by nucleolar factors such as nucleophosmin (NPM-1). In presence of cytoplasmic aggregation vital signaling processes were impaired, further destabilizing cellular homoeostasis. The mRNA accumulated in enlarged “nuclear RNA bodies”. Depletion of cytoplasmic mRNA consequently resulted in a reduction of protein synthesis. Impairment of nucleo-cytoplasmic transport caused by cytoplasmic protein aggregation may thus seriously aggravate the cellular pathology initiated by misfolding and aggregation in human amyloid diseases. Our findings suggest that novel therapeutic strategies may improve nucleocytoplasmic transport, utilize the nuclear proteostasis for aggregate removal, or increase the cellular resilience towards misfolded structures in general.Proteinmissfaltung und -aggregation wird mit neurodegenerativen Krankheiten wie Alzheimer, Parkinson und der Creutzfeldt-Jakob-Krankheit, sowie mit systemischen Amyloidosen in Verbindung gebracht. Auch wenn sich anfangs die Hauptbestandteile der Proteinaggregate krankheitsspezifisch unterscheiden, so kommt es bei den verschiedenen Demenzerkrankungen doch oft zu ähnlichen Symptomen und zellulären Fehlfunktionen. Eine nachhaltige Heilung ist bisher nicht möglich. Die Komplexität der auftretenden zellulären Fehlfunktionen erschwert eine klare Unterscheidung von primären Ursachen sowie deren Folgen und Nebenwirkungen. Um uns auf die toxischen Eigenschaften und die toxische Wirkung von missgefalteten Strukturen in Zellen zu konzentrieren, setzen wir eine Reihe von künstlichen β Proteinen ein, welche direkt amyloide Oligomere und Aggregate bilden. Die Toxizität der β Proteine trat sequenzabhängig in menschlichen, neuronalen, Pilz- und Bakterienzellen auf. Erhöhte Hydrophobie an der Proteinoberfläche und unstrukturierte Sequenzbereiche wurden als kritische strukturelle Merkmale der β Proteine und ihrer zellulären Interaktionspartner im Zusammenhang zur Toxizität identifiziert. Auch korrelierten kleinere, über das Zytoplasma verteilte Oligomere mit hoher Toxizität. Proteinaggregate treten in Patienten in verschiedenen Kompartimenten der Zelle und im extrazellulären Raum auf, oft an mehreren Stellen gleichzeitig. Um die Toxizität in verschiedenen Kompartimenten und deren Sensibilitäten zu untersuchen, schickten wir die β Proteine mittels Signalsequenzen gezielt in bestimmte zelluläre Kompartimente. Aggregation im Zytoplasma war hochtoxisch und störte den aktiven Transport zwischen Zytoplasma und Zellkern, einschließlich der Translokation von NF-κB und mRNA. Wir reproduzierten unsere Ergebnisse mit krankheitsassoziierten Mutanten von Huntingtin, TDP-43 und Parkin, welche vergleichbare Transportdefekte verursachten. Bemerkenswerterweise reduzierte sich die Toxizität der β Proteine stark, wenn sie in den Zellkern geschickt wurden. Hier sammelten sich die β Proteine in dichten Aggregaten in den Nukleoli. Dabei traten keine Transportprobleme auf. Nur Proteinaggregation im Zytoplasma verursachte (Ko-)Aggregation und Fehllokalisation zahlreicher zellulärer Proteine, besonders von solchen mit längeren unstrukturierten Bereichen. Dazu zählten auch Faktoren, welche den Transport von Proteinen und mRNA zwischen Zytoplasma und Zellkern vermitteln (Importin α und THOC Proteine). Die β Proteine im Zellkern verhielten sich im Gegensatz sehr unauffällig. Anscheinend wurden sie zusätzlich durch nukleoläre Faktoren wie Nukleophosmin (NPM-1) abgeschirmt. Aggregation im Zytoplasma beeinträchtigte die Übermittlung lebenswichtiger zellulärer Signale, was die zelluläre Homöostase weiter destabilisierte. Die mRNA hat sich dabei in vergrößerten „nukleären RNA Körperchen“ angesammelt. Die fehlende mRNA im Zytoplasma führte zu einer Abnahme der Proteinsynthese. Die von Proteinaggregaten verursachten Defekte im molekularen Transport zwischen Zytoplasma und Zellkern könnten so ernsthaft zur Verschlimmerung der zellulären Funktionsfähigkeit in neurodegenerativen und anderen Proteinfehlfaltungserkrankungen beitragen. Neue Therapieansätze könnten in einer Verbesserung des Kerntransports, in einer Verminderung von Aggregaten durch Proteostasissysteme im Zellkern, oder in einer generellen Stärkung der zellulären Resilienz gegenüber fehlgefalteten Proteinen zu finden sein

Protein Structure

Since the dawn of recorded history, and probably even before, men and women have been grasping at the mechanisms by which they themselves exist. Only relatively recently, did this grasp yield anything of substance, and only within the last several decades did the proteins play a pivotal role in this existence. In this expose on the topic of protein structure some of the current issues in this scientific field are discussed. The aim is that a non-expert can gain some appreciation for the intricacies involved, and in the current state of affairs. The expert meanwhile, we hope, can gain a deeper understanding of the topic

Bioinformatics

This book is divided into different research areas relevant in Bioinformatics such as biological networks, next generation sequencing, high performance computing, molecular modeling, structural bioinformatics, molecular modeling and intelligent data analysis. Each book section introduces the basic concepts and then explains its application to problems of great relevance, so both novice and expert readers can benefit from the information and research works presented here

Psr1p interacts with SUN/sad1p and EB1/mal3p to establish the bipolar spindle

Regular Abstracts - Sunday Poster Presentations: no. 382During mitosis, interpolar microtubules from two spindle pole bodies (SPBs) interdigitate to create an antiparallel microtubule array for accommodating numerous regulatory proteins. Among these proteins, the kinesin-5 cut7p/Eg5 is the key player responsible for sliding apart antiparallel microtubules and thus helps in establishing the bipolar spindle. At the onset of mitosis, two SPBs are adjacent to one another with most microtubules running nearly parallel toward the nuclear envelope, creating an unfavorable microtubule configuration for the kinesin-5 kinesins. Therefore, how the cell organizes the antiparallel microtubule array in the first place at mitotic onset remains enigmatic. Here, we show that a novel protein psrp1p localizes to the SPB and plays a key role in organizing the antiparallel microtubule array. The absence of psr1+ leads to a transient monopolar spindle and massive chromosome loss. Further functional characterization demonstrates that psr1p is recruited to the SPB through interaction with the conserved SUN protein sad1p and that psr1p physically interacts with the conserved microtubule plus tip protein mal3p/EB1. These results suggest a model that psr1p serves as a linking protein between sad1p/SUN and mal3p/EB1 to allow microtubule plus ends to be coupled to the SPBs for organization of an antiparallel microtubule array. Thus, we conclude that psr1p is involved in organizing the antiparallel microtubule array in the first place at mitosis onset by interaction with SUN/sad1p and EB1/mal3p, thereby establishing the bipolar spindle.postprin