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Research is the vital expression of humankind’s most important qualities: curiosity and imagination.

Explorers, inventors, pioneers—dedicated researchers on the frontiers of science and the humanities.

Insight, when it comes, changes everything.

Publications

The NOMIS community of researchers and partners is instrumental in driving interdisciplinary collaboration, generating insights and ultimately advancing our understanding of the world. A key component of these efforts is knowledge sharing. Comprising a unique offering of engaging scientific lectures, insightful films about our awardees’ research, and a comprehensive publication database, NOMIS Insights are designed to facilitate the sharing of knowledge. They showcase the groundbreaking findings and innovative perspectives born from NOMIS-supported research endeavors, embodying our dedication to enabling scientific progress.

Our NOMIS Insight database provides a comprehensive source of all publications resulting from NOMIS-supported research projects.

Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS/FTD

NOMIS Researcher(s)

Published in

April 15, 2020

The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72-specific pathology and TDP-43 pathology linked to neurodegeneration hinders targeted therapeutic development. Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly-GA promoted cytoplasmic mislocalization and aggregation of TDP-43 non-cell-autonomously, and anti-GA antibodies ameliorated TDP-43 mislocalization in both donor and receiver cells. Cell-to-cell transmission of poly-GA inhibited proteasome function in neighboring cells. Importantly, proteasome inhibition led to the accumulation of TDP-43 ubiquitinated within the nuclear localization signal (NLS) at lysine 95. Mutagenesis of this ubiquitination site completely blocked poly-GA-dependent mislocalization of TDP-43. Boosting proteasome function with rolipram reduced both poly-GA and TDP-43 aggregation. Our data from cell lines, primary neurons, transgenic mice, and patient tissue suggest that poly-GA promotes TDP-43 aggregation by inhibiting the proteasome cell-autonomously and non-cell-autonomously, which can be prevented by inhibiting poly-GA transmission with antibodies or boosting proteasome activity with rolipram.

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

DOI
10.15252/embj.2019102811

Child health as human capital

NOMIS Researcher(s)

Published in

April 1, 2020

Child health is increasingly understood to be a critical form of human capital, but only recently have we begun to understand how valuable it is and how its development could be better supported. This article provides an overview of recent work that demonstrates the key role of public insurance in supporting longer term human capital development and points to improvements in child mental health as an especially important mechanism.

Research field(s)
Health Sciences, Public Health & Health Services, Health Policy & Services

DOI
10.1002/hec.3995

Phase separation directs ubiquitination of gene-body nucleosomes

NOMIS Researcher(s)

Published in

March 26, 2020

The conserved yeast E3 ubiquitin ligase Bre1 and its partner, the E2 ubiquitin-conjugating enzyme Rad6, monoubiquitinate histone H2B across gene bodies during the transcription cycle1. Although processive ubiquitination might—in principle—arise from Bre1 and Rad6 travelling with RNA polymerase II2, the mechanism of H2B ubiquitination across genic nucleosomes remains unclear. Here we implicate liquid–liquid phase separation3 as the underlying mechanism. Biochemical reconstitution shows that Bre1 binds the scaffold protein Lge1, which possesses an intrinsically disordered region that phase-separates via multivalent interactions. The resulting condensates comprise a core of Lge1 encapsulated by an outer catalytic shell of Bre1. This layered liquid recruits Rad6 and the nucleosomal substrate, which accelerates the ubiquitination of H2B. In vivo, the condensate-forming region of Lge1 is required to ubiquitinate H2B in gene bodies beyond the +1 nucleosome. Our data suggest that layered condensates of histone-modifying enzymes generate chromatin-associated ‘reaction chambers’, with augmented catalytic activity along gene bodies. Equivalent processes may occur in human cells, and cause neurological disease when impaired.

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

DOI
10.1038/s41586-020-2097-z

A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation

NOMIS Researcher(s)

Published in

March 19, 2020

Selective autophagy of organelles is critical for cellular differentiation, homeostasis, and organismal health. Autophagy of the ER (ER-phagy) is implicated in human neuropathy but is poorly understood beyond a few autophagosomal receptors and remodelers. By using an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidence human ER-phagy factors. Two pathways were unexpectedly required for ER-phagy. First, reduced mitochondrial metabolism represses ER-phagy, which is opposite of general autophagy and is independent of AMPK. Second, ER-localized UFMylation is required for ER-phagy to repress the unfolded protein response via IRE1α. The UFL1 ligase is brought to the ER surface by DDRGK1 to UFMylate RPN1 and RPL26 and preferentially targets ER sheets for degradation, analogous to PINK1-Parkin regulation during mitophagy. Our data provide insight into the cellular logic of ER-phagy, reveal parallels between organelle autophagies, and provide an entry point to the relatively unexplored process of degrading the ER network.

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

DOI
10.1016/j.cell.2020.02.017

Joining a group diverts regret and responsibility away from the individual

NOMIS Researcher(s)

Published in

March 11, 2020

It has recently been proposed that a key motivation for joining groups is the protection from the negative consequences of undesirable outcomes. To test this claim, we investigated how experienced outcomes triggering loss and regret impacted people’s tendency to decide alone or join a group, and how decisions differed when voluntarily made alone versus in group. Replicated across two experiments, participants (n = 125 and n = 496) selected whether to play alone or contribute their vote to a group decision. Next, they chose between two lotteries with different probabilities of winning and losing. The higher the negative outcome, the more participants switched from deciding alone to with others. When joining a group to choose the lottery, choices were less driven by outcome and regret anticipation. Moreover, negative outcomes experienced alone, not part of a group vote, led to worse subsequent choices than positive outcomes. These results suggest that the protective shield of the collective reduces the influence of negative emotions that may help individuals re-evaluate past choices.

Research field(s)
Natural Sciences, Biology, Evolutionary Biology

DOI
10.1098/rspb.2019.2251

Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins

NOMIS Researcher(s)

Published in

March 10, 2020

In amyotrophic lateral sclerosis (ALS) motor neurons (MNs) undergo dying-back, where the distal axon degenerates before the soma. The hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS, but the mechanism of pathogenesis is largely unknown with both gain- and loss-of-function mechanisms being proposed. To better understand C9ORF72-ALS pathogenesis, we generated isogenic induced pluripotent stem cells. MNs with HRE in C9ORF72 showed decreased axonal trafficking compared with gene corrected MNs. However, knocking out C9ORF72 did not recapitulate these changes in MNs from healthy controls, suggesting a gain-of-function mechanism. In contrast, knocking out C9ORF72 in MNs with HRE exacerbated axonal trafficking defects and increased apoptosis as well as decreased levels of HSP70 and HSP40, and inhibition of HSPs exacerbated ALS phenotypes in MNs with HRE. Therefore, we propose that the HRE in C9ORF72 induces ALS pathogenesis via a combination of gain- and loss-of-function mechanisms. Sterneckert and colleagues generated isogenic induced pluripotent stem cell lines and demonstrated that MNs with hexanucleotide repeat expansion (HRE) in C9ORF72 show reduced axonal trafficking, which is not recapitulated by knocking out C9ORF72 in MNs from healthy individuals. In contrast, knocking out C9ORF72 exacerbated phenotypes in MNs with HRE, suggesting that both gain- and loss-of-function mechanisms contribute to C9ORF72-ALS.

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

DOI
10.1016/j.stemcr.2020.01.010

Fully automated, sequential focused ion beam milling for cryo-electron tomography

NOMIS Researcher(s)

Published in

March 1, 2020

Cryo-electron tomography (cryoET) has become a powerful technique at the interface of structural biology and cell biology, due to its unique ability for imaging cells in their native state and determining structures of macromolecular complexes in their cellular context. A limitation of cryoET is its restriction to relatively thin samples. Sample thinning by cryo-focused ion beam (cryoFIB) milling has significantly expanded the range of samples that can be analyzed by cryoET. Unfortunately, cryoFIB milling is low-throughput, time-consuming and manual. Here, we report a method for fully automated sequential cryoFIB preparation of high-quality lamellae, including rough milling and polishing. We reproducibly applied this method to eukaryotic and bacterial model organisms, and show that the resulting lamellae are suitable for cryoET imaging and subtomogram averaging. Since our method reduces the time required for lamella preparation and minimizes the need for user input, we envision the technique will render previously inaccessible projects feasible.

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

DOI
10.7554/eLife.52286

β-adrenoreceptors and the risk of Parkinson’s disease

NOMIS Researcher(s)

Published in

March 1, 2020

Background: β-adrenoceptors are widely expressed in different human organs, mediate important body functions and are targeted by medications for various diseases (such as coronary heart disease and heart attack) and many β-adrenoceptor acting drugs are listed on the WHO Model List of Essential Medicines. β-adrenoceptor antagonists are used by billions of patients with neurological disorders, primarily for the treatment of migraine and action tremor (mainly essential tremor), worldwide. Recent developments: An observational study reported a link between the chronic use of the β-adrenoceptor antagonist propranolol and an increased risk of Parkinson’s disease, while the chronic use of the β-adrenoceptor agonists was associated with a decreased risk. Further support of this association was provided by a dose-dependent decrease in the risk of Parkinson’s disease with chronic β-adrenoceptor agonist (eg, salbutamol) use, and by functional data indicating a possible underlying molecular mechanism. Five additional epidemiological studies have examined the modulation of the risk of Parkinson’s disease as a result of the use of β-adrenoceptor-acting drugs in different populations. Overall, similar estimates but different interpretations of the associations were provided. Several findings suggest that the increase in risk of Parkinson’s disease associated with β-adrenoceptor antagonists use can be explained by reverse causation because prodromal Parkinson’s disease is often associated with non-specific action tremor, which is usually treated with propranolol. The lower risk of Parkinson’s disease seen in patients receiving β-adrenoceptor agonists is likely to be indirectly mediated by smoking because smoking has a strong inverse association with Parkinson’s disease (people that smoke have a reduced risk of developing Parkinson’s disease). Smoking also causes chronic obstructive pulmonary disease, which is treated with β-adrenoceptor-agonist medications. Even if causal, the effect of β-adrenoceptor antagonists on the risk of Parkinson’s disease would be small compared with other Parkinson’s disease risk factors and would be similar to the risk evoked by pesticide exposure. The estimated risk of Parkinson’s disease because of β-adrenoceptor antagonists use corresponds to one case in 10 000 patients after 5 years of propranolol use, and would be considered a very rare adverse effect. Thus, not using β-adrenoceptor antagonists would severely harm patients with recommended indications, such as heart disease or migraine. Similarly, 50 000 people would have to be treated for 5 years with salbutamol to prevent Parkinson’s disease in one patient, suggesting that primary preventive therapy studies on disease modification are not warranted. Where next?: Epidemiological evidence for a causal relationship between use of β2-adrenoceptor antagonists and the increased risk of Parkinson’s disease is weak, with other explanations for the association being more probable. Future observational studies are warranted to clarify this association. However, given the very low risk associated with propranolol, most clinicians are unlikely to change their treatment approach.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1016/S1474-4422(19)30400-4

Adolescents with developmental dyscalculia do not have a generalized magnitude deficit – Processing of discrete and continuous magnitudes

NOMIS Researcher(s)

Published in

March 1, 2020

The link between number and space has been discussed in the literature for some time, resulting in the theory that number, space and time might be part of a generalized magnitude system. To date, several behavioral and neuroimaging findings support the notion of a generalized magnitude system, although contradictory results showing a partial overlap or separate magnitude systems are also found. The possible existence of a generalized magnitude processing area leads to the question how individuals with developmental dyscalculia (DD), known for deficits in numerical-arithmetical abilities, process magnitudes. By means of neuropsychological tests and functional magnetic resonance imaging (fMRI) we aimed to examine the relationship between number and space in typical and atypical development. Participants were 16 adolescents with DD (14.1 years) and 14 typically developing (TD) peers (13.8 years). In the fMRI paradigm participants had to perform discrete (arrays of dots) and continuous magnitude (angles) comparisons as well as a mental rotation task. In the neuropsychological tests, adolescents with dyscalculia performed significantly worse in numerical and complex visuo-spatial tasks. However, they showed similar results to TD peers when making discrete and continuous magnitude decisions during the neuropsychological tests and the fMRI paradigm. A conjunction analysis of the fMRI data revealed commonly activated higher order visual (inferior and middle occipital gyrus) and parietal (inferior and superior parietal lobe) magnitude areas for the discrete and continuous magnitude tasks. Moreover, no differences were found when contrasting both magnitude processing conditions, favoring the possibility of a generalized magnitude system. Group comparisons further revealed that dyscalculic subjects showed increased activation in domain general regions, whilst TD peers activate domain specific areas to a greater extent. In conclusion, our results point to the existence of a generalized magnitude system in the occipito-parietal stream in typical development. The detailed investigation of spatial and numerical magnitude abilities in DD reveals that the deficits in number processing and arithmetic cannot be explained with a general magnitude deficiency. Our results further indicate that multiple neuro-cognitive components might contribute to the explanation of DD.

Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Experimental Psychology

DOI
10.3389/fnhum.2017.00102

Fibroblast Growth Factor 2-Mediated Regulation of Neuronal Exosome Release Depends on VAMP3/Cellubrevin in Hippocampal Neurons

NOMIS Researcher(s)

Published in

March 1, 2020

Extracellular vesicles (EVs) are endogenous membrane-derived vesicles that shuttle bioactive molecules between glia and neurons, thereby promoting neuronal survival and plasticity in the central nervous system (CNS) and contributing to neurodegenerative conditions. Although EVs hold great potential as CNS theranostic nanocarriers, the specific molecular factors that regulate neuronal EV uptake and release are currently unknown. A combination of patch-clamp electrophysiology and pH-sensitive dye imaging is used to examine stimulus-evoked EV release in individual neurons in real time. Whereas spontaneous electrical activity and the application of a high-frequency stimulus induce a slow and prolonged fusion of multivesicular bodies (MVBs) with the plasma membrane (PM) in a subset of cells, the neurotrophic factor basic fibroblast growth factor (bFGF) greatly increases the rate of stimulus-evoked MVB-PM fusion events and, consequently, the abundance of EVs in the culture medium. Proteomic analysis of neuronal EVs demonstrates bFGF increases the abundance of the v-SNARE vesicle-associated membrane protein 3 (VAMP3, cellubrevin) on EVs. Conversely, knocking-down VAMP3 in cultured neurons attenuates the effect of bFGF on EV release. The results determine the temporal characteristics of MVB-PM fusion in hippocampal neurons and reveal a new function for bFGF signaling in controlling neuronal EV release.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Nanoscience & Nanotechnology

DOI
10.1002/advs.201902372

A Method for Producing Highly Pure Magnetosomes in Large Quantity for Medical Applications Using Magnetospirillum gryphiswaldense MSR-1 Magnetotactic Bacteria Amplified in Minimal Growth Media

NOMIS Researcher(s)

Published in

February 18, 2020

We report the synthesis in large quantity of highly pure magnetosomes for medical applications. For that, magnetosomes are produced by MSR-1 Magnetospirillum gryphiswaldense magnetotactic bacteria using minimal growth media devoid of uncharacterized and toxic products prohibited by pharmaceutical regulation, i.e., yeast extract, heavy metals different from iron, and carcinogenic, mutagenic and reprotoxic agents. This method follows two steps, during which bacteria are first pre-amplified without producing magnetosomes and are then fed with an iron source to synthesize magnetosomes, yielding, after 50 h of growth, an equivalent OD565 of ~8 and 10 mg of magnetosomes in iron per liter of growth media. Compared with magnetosomes produced in non-minimal growth media, those particles have lower concentrations in metals other than iron. Very significant reduction or disappearance in magnetosome composition of zinc, manganese, barium, and aluminum are observed. This new synthesis method paves the way towards the production of magnetosomes for medical applications.

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

DOI
10.3389/fbioe.2020.00016

Active poly-GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model

NOMIS Researcher(s)

Published in

February 7, 2020

The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non-canonical translation of the expanded repeat results in abundant poly-GA inclusion pathology throughout the CNS. (GA)149-CFP expression in mice triggers motor deficits and neuroinflammation. Since poly-GA is transmitted between cells, we investigated the therapeutic potential of anti-GA antibodies by vaccinating (GA)149-CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin-(GA)10 conjugates and pre-aggregated carrier-free (GA)15. Only ovalbumin-(GA)10 immunization induced a strong anti-GA response. The resulting antisera detected poly-GA aggregates in cell culture and patient tissue. Ovalbumin-(GA)10 immunization largely rescued the motor function in (GA)149-CFP transgenic mice and reduced poly-GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin-(GA)10-immunized poly-GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP-43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers.

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

DOI
10.15252/emmm.201910919

NG2 glia are required for maintaining microglia homeostatic state

NOMIS Researcher(s)

Published in

February 1, 2020

Microglia play vital roles in the health and diseases of the central nervous system. Loss of microglia homeostatic state is a key feature of brain aging and neurodegeneration. However, the mechanisms underlying the maintenance of distinct microglia cellular states are largely unclear. Here, we show that NG2 glia, also known as oligodendrocyte precursor cells, are essential for maintaining the homeostatic microglia state. We developed a highly efficient and selective NG2 glia depletion method using small-molecule inhibitors of platelet-derived growth factor (PDGF) signaling in cultured brain slices. We found that loss of NG2 glia abolished the homeostatic microglia signature without affecting the disease-associated microglia profiles. Similar findings were also observed in vivo by genetically depleting NG2 glia or conditionally inhibiting NG2 glia PDGF signaling in the adult mouse brain. These data suggest that NG2 glia exert a crucial influence onto microglia cellular states that are relevant to brain aging and neurodegenerative diseases. In addition, our results provide a powerful, convenient, and selective tool for the investigation of NG2 glia function.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1002/glia.23721

Metabolic Adaptations to Infections at the Organismal Level

NOMIS Researcher(s)

Published in

February 1, 2020

Metabolic processes occurring during host–microbiota–pathogen interactions can favorably or negatively influence host survival during infection. Defining the metabolic needs of the three players, the mechanisms through which they acquire nutrients, and whether each participant cooperates or competes with each other to meet their own metabolic demands during infection has the potential to reveal new approaches to treat disease. Here, we review topical findings in organismal metabolism and infection and highlight four emerging lines of investigation: how host–microbiota metabolic partnerships protect against infection; competition for glucose between host and pathogen; significance of infection-induced anorexia; and redefinition of the role of iron during infection. We also discuss how these discoveries shape our understanding of infection biology and their likely therapeutic value.

Research field(s)
Health Sciences, Clinical Medicine, Immunology

DOI
10.1016/j.it.2019.12.001

Alpha-synuclein fragments trigger distinct aggregation pathways

NOMIS Researcher(s)

Published in

February 1, 2020

Aggregation of alpha-synuclein (αSyn) is a crucial event underlying the pathophysiology of synucleinopathies. The existence of various intracellular and extracellular αSyn species, including cleaved αSyn, complicates the quest for an appropriate therapeutic target. Hence, to develop efficient disease-modifying strategies, it is fundamental to achieve a deeper understanding of the relevant spreading and toxic αSyn species. Here, we describe comparative and proof-of-principle approaches to determine the involvement of αSyn fragments in intercellular spreading. We demonstrate that two different αSyn fragments (1–95 and 61–140) fulfill the criteria of spreading species. They efficiently instigate formation of proteinase-K-resistant aggregates from cell-endogenous full-length αSyn, and drive it into different aggregation pathways. The resulting aggregates induce cellular toxicity. Strikingly, these aggregates are only detectable by specific antibodies. Our results suggest that αSyn fragments might be relevant not only for spreading, but also for aggregation-fate determination and differential strain formation.

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

DOI
10.1038/s41419-020-2285-7

Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration

NOMIS Researcher(s)

Published in

February 1, 2020

A rapidly ageing population and a limited therapeutic toolbox urgently necessitate new approaches to treat neurodegenerative diseases. Brain ageing, the key risk factor for neurodegeneration, involves complex cellular and molecular processes that eventually result in cognitive decline. Although cell-intrinsic defects in neurons and glia may partially explain this decline, cell-extrinsic changes in the systemic environment, mediated by blood, have recently been shown to contribute to brain dysfunction with age. Here, we review the current understanding of how systemic factors mediate brain ageing, how these factors are regulated and how we can translate these findings into therapies for neurodegenerative diseases.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1038/s41583-019-0255-9

Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain

NOMIS Researcher(s)

Published in

February 1, 2020

Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call ‘lipid-droplet-accumulating microglia’ (LDAM), are defective in phagocytosis, produce high levels of reactive oxygen species and secrete proinflammatory cytokines. RNA-sequencing analysis of LDAM revealed a transcriptional profile driven by innate inflammation that is distinct from previously reported microglial states. An unbiased CRISPR–Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin (GRN), are causes of autosomal-dominant forms of human neurodegenerative diseases. We therefore propose that LDAM contribute to age-related and genetic forms of neurodegeneration.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1038/s41593-019-0566-1

Loss of fragile X mental retardation protein precedes Lewy pathology in Parkinson’s disease

NOMIS Researcher(s)

Published in

February 1, 2020

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the gradual appearance of α-synuclein (α-syn)-containing neuronal protein aggregates. Although the exact mechanism of α-syn-mediated cell death remains elusive, recent research suggests that α-syn-induced alterations in neuronal excitability contribute to cell death in PD. Because the fragile X mental retardation protein (FMRP) controls the expression and function of numerous neuronal genes related to neuronal excitability and synaptic function, we here investigated the role of FMRP in α-syn-associated pathological changes in cell culture and mouse models of PD as well as in post-mortem human brain tissue from PD patients. We found FMRP to be decreased in cultured DA neurons and in the mouse brain in response to α-syn overexpression. FMRP was, furthermore, lost in the SNc of PD patients and in patients with early stages of incidental Lewy body disease (iLBD). Unlike fragile X syndrome (FXS), FMR1 expression in response to α-syn was regulated by a mechanism involving Protein Kinase C (PKC) and cAMP response element-binding protein (CREB). Reminiscent of FXS neurons, α-syn-overexpressing cells exhibited an increase in membrane N-type calcium channels, increased phosphorylation of ERK1/2, eIF4E and S6, increased overall protein synthesis, and increased expression of Matrix Metalloproteinase 9 (MMP9). FMRP affected neuronal function in a PD animal model, because FMRP-KO mice were resistant to the effect of α-syn on striatal dopamine release. In summary, our results thus reveal a new role of FMRP in PD and support the examination of FMRP-regulated genes in PD disease progression.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1007/s00401-019-02099-5

Nup93 regulates breast tumor growth by modulating cell proliferation and actin cytoskeleton remodeling

NOMIS Researcher(s)

Published in

January 20, 2020

Nucleoporin 93 (Nup93) expression inversely correlates with the survival of triple-negative breast cancer patients. However, our knowledge of Nup93 function in breast cancer besides its role as structural component of the nuclear pore complex is not understood. Combination of functional assays and genetic analyses suggested that chromatin interaction of Nup93 partially modulates the expression of genes associated with actin cytoskeleton remodeling and epithelial to mesenchymal transition, resulting in impaired invasion of triple-negative, claudin-low breast cancer cells. Nup93 depletion induced stress fiber formation associated with reduced cell migration/proliferation and impaired expression of mesenchymal-like genes. Silencing LIMCH1, a gene responsible for actin cytoskeleton remodeling and up-regulated upon Nup93 depletion, partially restored the invasive phenotype of cancer cells. Loss of Nup93 led to significant defects in tumor establishment/propagation in vivo, whereas patient samples revealed that high Nup93 and low LIMCH1 expression correlate with late tumor stage. Our approach identified Nup93 as contributor of triple-negative, claudin-low breast cancer cell invasion and paves the way to study the role of nuclear envelope proteins during breast cancer tumorigenesis.

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

DOI
10.26508/LSA.201900623

Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules

NOMIS Researcher(s)

Published in

January 17, 2020

Insoluble, hyperubiquitylated TAR DNA-binding protein of 43 kDa (TDP-43) in the central nervous system characterizes frontotemporal dementia and ALS in many individuals with these neurodegenerative diseases. The causes for neuropathological TDP-43 aggregation are unknown, but it has been suggested that stress granule (SG) formation is important in this process. Indeed, in human embryonic kidney HEK293E cells, various SG-forming conditions induced very strong TDP-43 ubiquitylation, insolubility, and reduced splicing activity. Osmotic stress-induced SG formation and TDP-43 ubiquitylation occurred rapidly and coincided with colocalization of TDP-43 and SG markers. Washout experiments confirmed the rapid dissolution of SGs, accompanied by normalization of TDP-43 ubiquitylation and solubility. Surprisingly, interference with the SG process using a protein kinase R-like endoplasmic reticulum kinase inhibitor (GSK2606414) or the translation blocker emetine did not prevent TDP-43 ubiquitylation and insolubility. Thus, parallel pathways may lead to pathological TDP-43 modifications independent of SG formation. Using a panel of kinase inhibitors targeting signaling pathways of the osmotic shock inducer sorbitol, we could largely rule out the stress-activated and extracellular signal-regulated protein kinase modules and glycogen synthase kinase 3β. For arsenite, but not for sorbitol, quenching oxidative stress with N-acetylcysteine did suppress both SG formation and TDP-43 ubiquitylation and insolubility. Thus, sodium arsenite appears to promote SG formation and TDP-43 modifications via oxidative stress, but sorbitol stimulates TDP-43 ubiquitylation and insolubility via a novel pathway(s) independent of SG formation. In conclusion, pathological TDP-43 modifications can be mediated via multiple distinct pathways for which SGs are not essential.

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

DOI
10.1074/jbc.RA119.010617

Wearing your heart on your screen: Investigating congruency-effects in autonomic responses and their role in interoceptive processing during biofeedback

NOMIS Researcher(s)

Published in

January 1, 2020

The experience of one’s embodied sense of self is dependent on the integration of signals originating both from within and outwith one’s body. During the processing and integration of these signals, the bodily self must maintain a fine balance between stability and malleability. Here we investigate the potential role of autonomic responses in interoceptive processing and their contribution to the stability of the bodily self. Using a biofeedback paradigm, we manipulated the congruency of cardiac signals across two hierarchical levels: (i) the low-level congruency between a visual feedback and participant’s own cardiac signal and (ii) the high-level congruency between the participants’ beliefs about the identity of the cardiac feedback and its true identity. We measured the effects of these manipulations on high-frequency heart rate variability (HF-HRV), a selective index of phasic vagal cardiac control. In Experiment 1, HF-HRV was sensitive to low-level congruency, independently of whether participants attempted to regulate or simply attend to the biofeedback. Experiment 2 revealed a higher-level congruency effect, as participants’ prior veridical beliefs increased HF-HRV while when false they decreased HF-HRV. Our results demonstrate that autonomic changes in HF-HRV are sensitive to congruencies across multiple hierarchical levels. Our findings have important theoretical implications for predictive coding models of the self as they pave the way for a more direct way to track the subtle changes in the co-processing of the internal and external milieus.

Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Experimental Psychology

DOI
10.1016/j.cognition.2019.104053

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