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Publications in Biomedical Research by NOMIS researchers

Nucleolar expansion and elevated protein translation in premature aging

NOMIS Researcher(s)

Published in

December 1, 2017

Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41467-017-00322-z

Ancestral Circuits for the Coordinated Modulation of Brain State

NOMIS Researcher(s)

Published in

November 30, 2017

Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. We used this method (MultiMAP) to record from 22 neuromodulatory cell types in behaving zebrafish during a reaction-time task that reports alertness. We identified multiple monoaminergic, cholinergic, and peptidergic cell types linked to alertness and found that activity in these cell types was mutually correlated during heightened alertness. We next recorded from and controlled homologous neuromodulatory cells in mice; alertness-related cell-type dynamics exhibited striking evolutionary conservation and modulated behavior similarly. These experiments establish a method for unbiased discovery of cellular elements underlying behavior and reveal an evolutionarily conserved set of diverse neuromodulatory systems that collectively govern internal state. Registration of brain-wide activity measurements with multiple molecular markers at cellular resolution uncovers multiple diverse neuromodulatory pathways linked to brain state.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.cell.2017.10.021

The form and function of channelrhodopsin

NOMIS Researcher(s)

Published in

September 15, 2017

Channelrhodopsins are light-gated ion channels that, via regulation of flagellar function, enable single-celled motile algae to seek ambient light conditions suitable for photosynthesis and survival. These plant behavioral responses were initially investigated more than 150 years ago. Recently, major principles of function for light-gated ion channels have been elucidated by creating channelrhodopsins with kinetics that are accelerated or slowed over orders of magnitude, by discovering and designing channelrhodopsins with altered spectral properties, by solving the high-resolution channelrhodopsin crystal structure, and by structural model–guided redesign of channelrhodopsins for altered ion selectivity. Each of these discoveries not only revealed basic principles governing the operation of light-gated ion channels, but also enabled the creation of new proteins for illuminating, via optogenetics, the fundamentals of brain function.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1126/science.aan5544

Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD

NOMIS Researcher(s)

Published in

July 1, 2017

The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non-conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain-of-function mechanism. Here, we established a poly-GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly-GP levels were already detectable in asymptomatic C9orf72 mutation carriers compared to healthy controls and patients with other neurodegenerative diseases. The poly-GP levels in asymptomatic carriers were similar to symptomatic c9ALS/FTD cases. Poly-GP levels were not correlated with disease onset, clinical scores, and CSF levels of neurofilaments as a marker for axonal damage. Poly-GP determination in CSF revealed a C9orf72 mutation carrier in our cohort and may thus be used as a diagnostic marker in addition to genetic testing to screen patients. Presymptomatic expression of poly-GP and likely other DPR species may contribute to disease onset and thus represents an alluring therapeutic target.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.15252/emmm.201607486

Cbp80 is needed for the expression of piRNA components and piRNAs

NOMIS Researcher(s)

Published in

July 1, 2017

Cap binding protein 80 (Cbp80) is the larger subunit of the nuclear cap-binding complex (nCBC), which is known to play important roles in nuclear mRNA processing, export, stability and quality control events. Reducing Cbp80 mRNA levels in the female germline revealed that Cbp80 is also involved in defending the germline against transposable elements. Combining such knockdown experiments with large scale sequencing of small RNAs further showed that Cbp80 is involved in the initial biogenesis of piRNAs as well as in the secondary biogenesis pathway, the ping-pong amplification cycle. We further found that Cbp80 knockdown not only led to the upregulation of transposons, but also to delocalization of Piwi, Aub and Ago3, key factors in the piRNA biosynthesis pathway. Furthermore, compared to controls, levels of Piwi and Aub were also reduced upon knock down of Cbp80. On the other hand, with the same treatment we could not detect significant changes in levels or subcellular distribution (nuage localization) of piRNA precursor transcripts. This shows that Cbp80 plays an important role in the production and localization of the protein components of the piRNA pathway and it seems to be less important for the production and export of the piRNA precursor transcripts.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1371/journal.pone.0181743

Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins

NOMIS Researcher(s)

Published in

May 1, 2017

Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly-GA, poly-GP, and poly-PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly-GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly-GA and cerebellar extracts of C9orf72 patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80. Treatment with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity of C9orf72 brain extracts. Poly-GA-directed immunotherapy may thus reduce DPR aggregation and disease progression in C9orf72 ALS/FTD.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.15252/emmm.201607054

PERK activation mitigates tau pathology in vitro and in vivo

NOMIS Researcher(s)

Published in

March 1, 2017

The RNA-like endoplasmic reticulum kinase (PERK) is genetically associated with the tauopathy progressive supranuclear palsy (PSP). To elucidate the functional mechanisms underlying this association, we explored PERK activity in brains of PSP patients and its function in three tauopathy models (cultured human neurons overexpressing 4-repeat wild-type tau or treated with the environmental neurotoxin annonacin, and P301S tau transgenic mice). In vitro, treatment with a pharmacological PERK activator CCT020312 or PERK overexpression reduced tau phosphorylation, tau conformational change and 4-repeat tau isoforms, and increased cell viability. In vivo, the PERK activator significantly improved memory and locomotor function, reduced tau pathology, and prevented dendritic spine and motoneuron loss in P301S tau mice. Importantly, the PERK substrate EIF2A, mediating some detrimental effects of PERK signaling, was downregulated in PSP brains and tauopathy models, suggesting that the alternative PERK–NRF2 pathway accounts for these beneficial effects in the context of tauopathies. In summary, PERK activation may be a novel strategy to treat PSP and eventually other tauopathies.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.15252/emmm.201606664

Intraneuronal protein aggregation as a trigger for inflammation and neurodegeneration in the aging brain

NOMIS Researcher(s)

Published in

January 1, 2017

Age is, by far, the greatest risk factor for Alzheimer’s disease (AD) , yet few A Ddrug candidateshave been generated that target pathways specifically associated with the aging process itself. Two ubiquitous features of the aging brain are the intracellular accumulation of aggregated proteins and inflammation. As intraneuronal amyloid protein is detected before markers of inflammation, we argue that old, age-associated, aggregated proteins in neurons can induce inflammation, resulting inmultiple forms of brain toxicities. The consequence is the increased risk of old, age-associated, neurodegenerative diseases. As most of these diseases are associated with the accumulation of aggregated proteins, it is possible that any therapeutic that reduces intracellular protein aggregation will benefit all. – Currais, A., Fischer, W., Maher, P., Schubert, D. Intraneuronal protein aggregation as a trigger for inflammation and neurodegeneration in the aging brain.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1096/fj.201601184

In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration

NOMIS Researcher(s)

Published in

December 1, 2016

Targeted genome editing via engineered nucleases is an exciting area of biomedical research and holds potential for clinical applications. Despite rapid advances in the field, in vivo targeted transgene integration is still infeasible because current tools are inefficient, especially for non-dividing cells, which compose most adult tissues. This poses a barrier for uncovering fundamental biological principles and developing treatments for a broad range of genetic disorders. Based on clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) technology, here we devise a homology-independent targeted integration (HITI) strategy, which allows for robust DNA knock-in in both dividing and non-dividing cells in vitro and, more importantly, in vivo (for example, in neurons of postnatal mammals). As a proof of concept of its therapeutic potential, we demonstrate the efficacy of HITI in improving visual function using a rat model of the retinal degeneration condition retinitis pigmentosa. The HITI method presented here establishes new avenues for basic research and targeted gene therapies.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/nature20565

Disease Tolerance Trick or Treat: Give Your Brain Something Good to Eat

NOMIS Researcher(s)

Published in

September 8, 2016

The reprioritization of feeding motivations during disease is proposed to optimize host defense strategies against infection. Now, Wang et al. identify that sickness-induced anorexia differentially shapes the metabolic requirements of cellular stress adaptations, leading to opposite impact on disease tolerance upon bacterial versus viral infections.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.cell.2016.08.034

Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition

NOMIS Researcher(s)

Published in

September 1, 2016

Intronic hexanucleotide (G4C2) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins (DPR). Repeat-dependent toxicity may affect nuclear import. hnRNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G4C2 repeat RNA. We now report that a reduction of nuclear hnRNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hnRNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hnRNPA3. Reduced nuclear hnRNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.15252/embr.201541724

Minor intron splicing is regulated by FUS and affected by ALS-associated FUS mutants

NOMIS Researcher(s)

Published in

July 15, 2016

Fused in sarcoma (FUS) is a ubiquitously expressed RNA-binding protein proposed to function in various RNA metabolic pathways, including transcription regulation, pre-mRNA splicing, RNA transport and microRNA processing. Mutations in the FUS gene were identified in patients with amyotrophic lateral sclerosis (ALS), but the pathomechanisms by which these mutations cause ALS are not known. Here, we show that FUS interacts with the minor spliceosome constituent U11 snRNP, binds preferentially to minor introns and directly regulates their removal. Furthermore, a FUS knockout in neuroblastoma cells strongly disturbs the splicing of minor intron-containing mRNAs, among them mRNAs required for action potential transmission and for functional spinal motor units. Moreover, an ALS-associated FUS mutant that forms cytoplasmic aggregates inhibits splicing of minor introns by trapping U11 and U12 snRNAs in these aggregates. Collectively, our findings suggest a possible pathomechanism for ALS in which mutated FUS inhibits correct splicing of minor introns in mRNAs encoding proteins required for motor neuron survival.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.15252/embj.201593791

Cooperative microbial tolerance behaviors in host-microbiota mutualism

NOMIS Researcher(s)

Published in

June 2, 2016

Animal defense strategies against microbes are most often thought of as a function of the immune system, the primary function of which is to sense and kill microbes through the execution of resistance mechanisms. However, this antagonistic view creates complications for our understanding of beneficial host-microbe interactions. Pathogenic microbes are described as employing a few common behaviors that promote their fitness at the expense of host health and fitness. Here, a complementary framework is proposed to suggest that, in addition to pathogens, beneficial microbes have evolved behaviors to manipulate host processes in order to promote their own fitness and do so through the promotion of host health and fitness. In this Perspective, I explore the idea that patterns or behaviors traditionally ascribed to pathogenic microbes are also employed by beneficial microbes to promote host tolerance defense strategies. Such strategies would promote host health without having a negative impact on microbial fitness and would thereby yield cooperative evolutionary dynamics that are likely required to drive mutualistic co-evolution of hosts and microbes.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.cell.2016.05.049

Understanding the molecular mechanisms of reprogramming

NOMIS Researcher(s)

Published in

May 6, 2016

Despite the profound and rapid advancements in reprogramming technologies since the generation of the first induced pluripotent stem cells (iPSCs) in 2006[1], the molecular basics of the process and its implications are still not fully understood. Recent work has suggested that a subset of TFs, so called “Pioneer TFs”, play an important role during the stochastic phase of iPSC reprogramming [2-6]. Pioneer TFs activities differ from conventional transcription factors in their mechanism of action. They bind directly to condensed chromatin and elicit a series of chromatin remodeling events that lead to opening of the chromatin. Chromatin decondensation by pioneer factors progressively occurs during cell division and in turn exposes specific gene promoters in the DNA to which TFs can now directly bind to promoters that are readily accessible[2, 6]. Here, we will summarize recent advancements on our understanding of the molecular mechanisms underlying reprogramming to iPSC as well as the implications that pioneer Transcription Factor activities might play during different lineage conversion processes.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1016/j.bbrc.2015.11.120

Establishment of human iPSC-based models for the study and targeting of glioma initiating cells

NOMIS Researcher(s)

Published in

February 22, 2016

Glioma tumour-initiating cells (GTICs) can originate upon the transformation of neural progenitor cells (NPCs). Studies on GTICs have focused on primary tumours from which GTICs could be isolated and the use of human embryonic material. Recently, the somatic genomic landscape of human gliomas has been reported. RTK (receptor tyrosine kinase) and p53 signalling were found dysregulated in â1/490% and 86% of all primary tumours analysed, respectively. Here we report on the use of human-induced pluripotent stem cells (hiPSCs) for modelling gliomagenesis. Dysregulation of RTK and p53 signalling in hiPSC-derived NPCs (iNPCs) recapitulates GTIC properties in vitro. In vivo transplantation of transformed iNPCs leads to highly aggressive tumours containing undifferentiated stem cells and their differentiated derivatives. Metabolic modulation compromises GTIC viability. Last, screening of 101 anti-cancer compounds identifies three molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results highlight the potential of hiPSCs for studying human tumourigenesis.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/ncomms10743

Nuclear envelope rupture is induced by actin-based nucleus confinement

NOMIS Researcher(s)

Published in

January 1, 2016

Repeated rounds of nuclear envelope (NE) rupture and repair have been observed in laminopathy and cancer cells and result in intermittent loss of nucleus compartmentalization. Currently, the causes of NE rupture are unclear. Here, we show that NE rupture in cancer cells relies on the assembly of contractile actin bundles that interact with the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex. We found that the loss of actin bundles or the LINC complex did not rescue nuclear lamina defects, a previously identified determinant of nuclear membrane stability, but did decrease the number and size of chromatin hernias. Finally, NE rupture inhibition could be rescued in cells treated with actin-depolymerizing drugs by mechanically constraining nucleus height. These data suggest a model of NE rupture where weak membrane areas, caused by defects in lamina organization, rupture because of an increase in intranuclear pressure from actin-based nucleus confinement.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1083/jcb.201603053

Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells

NOMIS Researcher(s)

Published in

January 1, 2015

Billions of inflammatory leukocytes die and are phagocytically cleared each day. This regular renewal facilitates the normal termination of inflammatory responses, suppressing pro-inflammatory mediators and inducing their anti-inflammatory counterparts. Here we investigate the role of the receptor tyrosine kinase (RTK) Mer and its ligands Protein S and Gas6 in the initial recognition and capture of apoptotic cells (ACs) by macrophages. We demonstrate extremely rapid binding kinetics of both ligands to phosphatidylserine (PtdSer)-displaying ACs, and show that ACs can be co-opsonized with multiple PtdSer opsonins.We further show that macrophage phagocytosis of ACs opsonized with Mer ligands can occur independently of a requirement for αV integrins. Finally, we demonstrate a novel role for Mer in the tethering of ACs to the macrophage surface, and show that Mer-mediated tethering and subsequent AC engulfment can be distinguished by their requirement for Mer kinase activity. Our results identify Mer as a receptor uniquely capable of both tethering ACs to the macrophage surface and driving their subsequent internalization.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1038/cddis.2015.18

Sulfonation pathway inhibitors block reactivation of latent HIV-1

NOMIS Researcher(s)

Published in

December 1, 2014

Long-lived pools of latently infected cells are a significant barrier to the development of a cure for HIV-1 infection. A better understanding of the mechanisms of reactivation from latency is needed to facilitate the development of novel therapies that address this problem. Here we show that chemical inhibitors of the sulfonation pathway prevent virus reactivation, both in latently infected J-Lat and U1 cell lines and in a primary human CD4+ T cell model of latency. In each of these models, sulfonation inhibitors decreased transcription initiation from the HIV-1 promoter. These inhibitors block transcription initiation at a step that lies downstream of nucleosome remodeling and affects RNA polymerase II recruitment to the viral promoter. These results suggest that the sulfonation pathway acts by a novel mechanism to regulate efficient virus transcription initiation during reactivation from latency, and further that augmentation of this pathway could be therapeutically useful.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1016/j.virol.2014.08.016

CHD1 and CHD2 are positive regulators of HIV-1 gene expression

NOMIS Researcher(s)

Published in

October 8, 2014

Background: Retroviruses encode a very limited number of proteins and therefore must exploit a wide variety of host proteins for completion of their lifecycle. Methods: We performed an insertional mutagenesis screen to identify novel cellular regulators of retroviral replication. Results: This approach identified the ATP-dependent chromatin remodeler, chromodomain helicase DNA-binding protein 2 (CHD2), as well as the highly related CHD1 protein, as positive regulators of both MLV and HIV-1 replication in rodent and human cells. RNAi knockdown of either CHD2 or the related CHD1 protein, in human cells resulted in a block to infection by HIV-1, specifically at the level of transcription. Conclusions: These results demonstrate that CHD1 and CHD2 can act as positive regulators of HIV-1 gene expression.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1186/1743-422X-11-180

Reprogramming by lineage specifiers: Blurring the lines between pluripotency and differentiation

NOMIS Researcher(s)

Published in

October 1, 2014

The generation of human induced pluripotent stem cells (iPS) has raised enormous expectations within the biomedical community due to their potential vast implications in regenerative and personalized medicine. However, reprogramming to iPS is still not fully comprehended. Difficulties found in ascribing specific molecular patterns to pluripotent cells (PSCs), and inherent inter-line and intra-line variability between different PSCs need to be resolved. Additionally, and despite multiple assumptions, it remains unclear whether the current in vitro culturing conditions for the maintenance and differentiation of PSCs do indeed recapitulate the developmental processes observed in vivo. As a consequence, basic questions such as what is the actual nature of PSCs remain unanswered and different theories have emerged in regards to the identity of these valuable cell population. Here we discuss on the published theories for defining PSC identity, the implications that the different postulated models have for the reprogramming field as well as speculate on potential future directions that might be opened once a precise knowledge on the nature of PSCs is accomplished.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.gde.2014.09.009

Function of a foxp3 cis-element in protecting regulatory T cell identity

NOMIS Researcher(s)

Published in

August 14, 2014

The homeostasis of multicellular organisms requires terminally differentiated cells to preserve their lineage specificity. However, it is unclear whether mechanisms exist to actively protect cell identity in response to environmental cues that confer functional plasticity. Regulatory T (Treg) cells, specified by the transcription factor Foxp3, are indispensable for immune system homeostasis. Here, we report that conserved noncoding sequence 2 (CNS2), a CpG-rich Foxp3 intronic cis-element specifically demethylated in mature Tregs, helps maintain immune homeostasis and limit autoimmune disease development by protecting Treg identity in response to signals that shape mature Treg functions and drive their initial differentiation. In activated Tregs, CNS2 helps protect Foxp3 expression from destabilizing cytokine conditions by sensing TCR/NFAT activation, which facilitates the interaction between CNS2 and Foxp3 promoter. Thus, epigenetically marked cis-elements can protect cell identity by sensing key environmental cues central to both cell identity formation and functional plasticity without interfering with initial cell differentiation. © 2014 Elsevier Inc.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.cell.2014.07.030

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