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Publications in Health Sciences by NOMIS researchers

The Warburg Dance Movement Library—The WADAMO Library: A Validation Study

NOMIS Researcher(s)

Published in

January 1, 2019

The Warburg Dance Movement Library is a validated set of 234 video clips of dance movements for empirical research in the fields of cognitive science and neuroscience of action perception, affect perception and neuroaesthetics. The library contains two categories of video clips of dance movement sequences. Of each pair, one version of the movement sequence is emotionally expressive (Clip a), while the other version of the same sequence (Clip b) is not expressive but as technically correct as the expressive version (Clip a). We sought to complement previous dance video stimuli libraries. Facial information, colour and music have been removed, and each clip has been faded in and out. We equalised stimulus length (6 seconds, 8 counts in dance theory), the dancers’ clothing and video background and included both male and female dancers, and we controlled for technical correctness of movement execution. The Warburg Dance Movement Library contains both contemporary and ballet movements. Two online surveys (N = 160) confirmed the classification into the two categories of expressivity. Four additional online surveys (N = 80) provided beauty and liking ratings for each clip. A correlation matrix illustrates all variables of this norming study (technical correctness, expressivity, beauty, liking, luminance, motion energy).

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

DOI
10.1177/0301006618816631

Coaching from the sidelines: the nuclear periphery in genome regulation

NOMIS Researcher(s)

Published in

January 1, 2019

The genome is packaged and organized nonrandomly within the 3D space of the nucleus to promote efficient gene expression and to faithfully maintain silencing of heterochromatin. The genome is enclosed within the nucleus by the nuclear envelope membrane, which contains a set of proteins that actively participate in chromatin organization and gene regulation. Technological advances are providing views of genome organization at unprecedented resolution and are beginning to reveal the ways that cells co-opt the structures of the nuclear periphery for nuclear organization and gene regulation. These genome regulatory roles of proteins of the nuclear periphery have important influences on development, disease and ageing.

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

DOI
10.1038/s41576-018-0063-5

Unbiased Screens for Modifiers of Alpha-Synuclein Toxicity

NOMIS Researcher(s)

Published in

January 1, 2019

Purpose of Review: We provide an overview about unbiased screens to identify modifiers of alpha-synuclein (αSyn)-induced toxicity, present the models and the libraries that have been used for screening, and describe how hits from primary screens were selected and validated. Recent Findings: Screens can be classified as either genetic or chemical compound modifier screens, but a few screens do not fit this classification. Most screens addressing αSyn-induced toxicity, including genome-wide overexpressing and deletion, were performed in yeast. More recently, newer methods such as CRISPR-Cas9 became available and were used for screening purposes. Paradoxically, given that αSyn-induced toxicity plays a role in neurological diseases, there is a shortage of human cell-based models for screening. Moreover, most screens used mutant or fluorescently tagged forms of αSyn and only very few screens investigated wild-type αSyn. Particularly, no genome-wide αSyn toxicity screen in human dopaminergic neurons has been published so far. Summary: Most unbiased screens for modifiers of αSyn toxicity were performed in yeast, and there is a lack of screens performed in human and particularly dopaminergic cells.

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

DOI
10.1007/s11910-019-0925-z

FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress

NOMIS Researcher(s)

Published in

January 1, 2019

FUS (fused in sarcoma) plays a key role in several steps of RNA metabolism, and dominant mutations in this protein are associated with neurodegenerative diseases. Here, we show that FUS is a component of the cellular response to topoisomerase I (TOP1)–induced DNA breakage; relocalising to the nucleolus in response to RNA polymerase II (Pol II) stalling at sites of TOP1-induced DNA breaks. This relocalisation is rapid and dynamic, reversing following the removal of TOP1-induced breaks and coinciding with the recovery of global transcription. Importantly, FUS relocalisation following TOP1-induced DNA breakage is associated with increased FUS binding at sites of RNA polymerase I transcription in ribosomal DNA and reduced FUS binding at sites of RNA Pol II transcription, suggesting that FUS relocates from sites of stalled RNA Pol II either to regulate pre-mRNA processing during transcriptional stress or to modulate ribosomal RNA biogenesis. Importantly, FUS-mutant patient fibroblasts are hypersensitive to TOP1-induced DNA breakage, highlighting the possible relevance of these findings to neurodegeneration.

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

DOI
10.26508/lsa.201800222

The Alzheimer’s Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer’s disease

NOMIS Researcher(s)

Published in

January 1, 2019

Introduction: Alzheimer’s disease (AD) pathology, including the accumulation of amyloid beta (Aβ) species and tau pathology, begins decades before the onset of cognitive impairment. This long preclinical period provides an opportunity for clinical trials designed to prevent or delay the onset of cognitive impairment due to AD. Under the umbrella of the Alzheimer’s Prevention Initiative Generation Program, therapies targeting Aβ, including CNP520 (umibecestat), a β-site-amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitor, and CAD106, an active Aβ immunotherapy, are in clinical development in preclinical AD. Methods: The Alzheimer’s Prevention Initiative Generation Program comprises two pivotal (phase 2/3) studies that assess the efficacy and safety of umibecestat and CAD106 in cognitively unimpaired individuals with high risk for developing symptoms of AD based on their age (60–75 years), APOE4 genotype, and, for heterozygotes (APOE ε2/ε4 or ε3/ε4), elevated brain amyloid. Approximately, 3500 individuals will be enrolled in either Generation Study 1 (randomized to cohort 1 [CAD106 injection or placebo, 5:3] or cohort 2 [oral umibecestat 50 mg or placebo, 3:2]) or Generation Study 2 (randomized to oral umibecestat 50 mg and 15 mg, or placebo [2:1:2]). Participants receive treatment for at least 60 months and up to a maximum of 96 months. Primary outcomes include time to event, with event defined as diagnosis of mild cognitive impairment due to AD and/or dementia due to AD, and the Alzheimer’s Prevention Initiative preclinical composite cognitive test battery. Secondary endpoints include the Clinical Dementia Rating Sum of Boxes, Repeatable Battery for the Assessment of Neuropsychological Status total score, Everyday Cognition Scale, biomarkers, and brain imaging. Discussion: The Generation Program is designed to assess the efficacy, safety, and biomarker effects of the two treatments in individuals at high risk for AD. It may also provide a plausible test of the amyloid hypothesis and further accelerate the evaluation of AD prevention therapies.

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

DOI
10.1016/j.trci.2019.02.005

Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation

NOMIS Researcher(s)

Published in

December 1, 2018

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS.

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

DOI
10.1038/s41467-017-02299-1

Neurostructural correlate of math anxiety in the brain of children

NOMIS Researcher(s)

Published in

December 1, 2018

Adequate mathematical competencies are currently indispensable in professional and social life. However, mathematics is often associated with stress and frustration and the confrontation with tasks that require mathematical knowledge triggers anxiety in many children. We examined if there is a relationship between math anxiety and changes in brain structure in children with and without developmental dyscalculia. Our findings showed that math anxiety is related to altered brain structure. In particular, the right amygdala volume was reduced in individuals with higher math anxiety. In conclusion, math anxiety not only hinders children in arithmetic development, but it is associated with altered brain structure in areas related to fear processing. This emphasizes the far-reaching outcome emotional factors in mathematical cognition can have and encourages educators and researchers alike to consider math anxiety to prevent detrimental long-term consequences on school achievement and quality of life, especially in children with developmental dyscalculia.

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

DOI
10.1038/s41398-018-0320-6

Targeting repair pathways with small molecules increases precise genome editing in pluripotent stem cells

NOMIS Researcher(s)

Published in

December 1, 2018

A now frequently used method to edit mammalian genomes uses the nucleases CRISPR/Cas9 and CRISPR/Cpf1 or the nickase CRISPR/Cas9n to introduce double-strand breaks which are then repaired by homology-directed repair using DNA donor molecules carrying desired mutations. Using a mixture of small molecules, the “CRISPY” mix, we achieve a 2.8- to 7.2-fold increase in precise genome editing with Cas9n, resulting in the introduction of the intended nucleotide substitutions in almost 50% of chromosomes or of gene encoding a blue fluorescent protein in 27% of cells, to our knowledge the highest editing efficiency in human induced pluripotent stem cells described to date. Furthermore, the CRISPY mix improves precise genome editing with Cpf1 2.3- to 4.0-fold, allowing almost 20% of chromosomes to be edited. The components of the CRISPY mix do not always increase the editing efficiency in the immortalized or primary cell lines tested, suggesting that employed repair pathways are cell-type specific.

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

DOI
10.1038/s41467-018-04609-7

Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1

NOMIS Researcher(s)

Published in

December 1, 2018

Genetic, epigenetic, and environmental factors contribute to the multifactorial disorder progressive supranuclear palsy (PSP). Here, we study epigenetic changes by genome-wide analysis of DNA from postmortem tissue of forebrains of patients and controls and detect significant (P < 0.05) methylation differences at 717 CpG sites in PSP vs. controls. Four-hundred fifty-one of these sites are associated with protein-coding genes. While differential methylation only affects a few sites in most genes, DLX1 is hypermethylated at multiple sites. Expression of an antisense transcript of DLX1, DLX1AS, is reduced in PSP brains. The amount of DLX1 protein is increased in gray matter of PSP forebrains. Pathway analysis suggests that DLX1 influences MAPT-encoded Tau protein. In a cell system, overexpression of DLX1 results in downregulation of MAPT while overexpression of DLX1AS causes upregulation of MAPT. Our observations suggest that altered DLX1 methylation and expression contribute to pathogenesis of PSP by influencing MAPT.

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

DOI
10.1038/s41467-018-05325-y

K-variant BCHE and pesticide exposure: Gene-environment interactions in a case–control study of Parkinson’s disease in Egypt

NOMIS Researcher(s)

Published in

December 1, 2018

Pesticide exposure is associated with increased risk of Parkinson’s disease (PD). We investigated in Egypt whether common variants in genes involved in pesticide detoxification or transport might modify the risk of PD evoked by pesticide exposure. We recruited 416 PD patients and 445 controls. Information on environmental factors was collected by questionnaire-based structured interviews. Candidate single-nucleotide polymorphisms (SNPs) in 15 pesticide-related genes were genotyped. We analyzed the influence of environmental factors and SNPs as well as the interaction of pesticide exposure and SNPs on the risk of PD. The risk of PD was reduced by coffee consumption [OR = 0.63, 95% CI: 0.43–0.90, P = 0.013] and increased by pesticide exposure [OR = 7.09, 95% CI: 1.12–44.01, P = 0.036]. The SNP rs1126680 in the butyrylcholinesterase gene BCHE reduced the risk of PD irrespective of pesticide exposure [OR = 0.38, 95% CI: 0.20–0.70, P = 0.002]. The SNP rs1803274, defining K-variant BCHE, interacted significantly with pesticide exposure (P = 0.007) and increased the risk of PD only in pesticide-exposed individuals [OR = 2.49, 95% CI: 1.50–4.19, P = 0.0005]. The K-variant BCHE reduces serum activity of butyrylcholinesterase, a known bioscavenger for pesticides. Individuals with K-variant BCHE appear to have an increased risk for PD when exposed to pesticides.

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

DOI
10.1038/s41598-018-35003-4

Going at the heart of social cognition: is there a role for interoception in self-other distinction?

NOMIS Researcher(s)

Published in

December 1, 2018

Interoception describes the processing and awareness of bodily signals arising from visceral organs, essential for the organism’s homeostatic needs. Beyond homeostasis, the integration of exteroceptive and interoceptive signals is required for the coherence of bodily self-awareness. Here we suggest that interoception also plays a critical role in social cognition. Relating to others as individuals who are distinct from one’s self requires the simultaneous yet distinct co-representation of self and others. We propose that interoceptive awareness appears to stabilise the mental representation of one’s self as distinct from others. A more nuanced understanding of the role of interoception in the representation of others in relation to ourselves is vital to determine its importance in social cognition.

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

DOI
10.1016/j.copsyc.2018.04.008

New classification of tauopathies

NOMIS Researcher(s)

Published in

November 1, 2018

Tauopathies are a group of neurodegenerative diseases characterized by pathological intracellular deposits of the protein tau. Isoform composition, morphology and anatomical distribution of cellular tau-immunoreactivities are defining distinct tauopathies as molecular pathological disease entities. The clinical spectrum of tauopathies includes syndromes with primary motor symptoms and with primary cognitive dysfunction. The traditional syndrome-based classification is currently being complemented by a molecular-pathological classification. While the syndrome-based classification is helpful to select symptomatic therapies, and to generate clinical working hypotheses about underlying etiologies, the molecular-pathological classification is most important for the development and application of molecularly tailored disease-modifying therapies.

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

DOI
10.1016/j.neurol.2018.07.001

Being a Beast Machine: The Somatic Basis of Selfhood

NOMIS Researcher(s)

Published in

November 1, 2018

Modern psychology has long focused on the body as the basis of the self. Recently, predictive processing accounts of interoception (perception of the body ‘from within’) have become influential in accounting for experiences of body ownership and emotion. Here, we describe embodied selfhood in terms of ‘instrumental interoceptive inference’ that emphasises allostatic regulation and physiological integrity. We apply this approach to the distinctive phenomenology of embodied selfhood, accounting for its non-object-like character and subjective stability over time. Our perspective has implications for the development of selfhood and illuminates longstanding debates about relations between life and mind, implying, contrary to Descartes, that experiences of embodied selfhood arise because of, and not in spite of, our nature as ‘beast machines’.

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

DOI
10.1016/j.tics.2018.08.008

Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris

NOMIS Researcher(s)

Published in

October 18, 2018

Here we present a compendium of single-cell transcriptomic data from the model organism Mus musculus that comprises more than 100,000 cells from 20 organs and tissues. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations and enable the direct and controlled comparison of gene expression in cell types that are shared between tissues, such as T lymphocytes and endothelial cells from different anatomical locations. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3′-end counting, enabled the survey of thousands of cells at relatively low coverage, whereas the other, full-length transcript analysis based on fluorescence-activated cell sorting, enabled the characterization of cell types with high sensitivity and coverage. The cumulative data provide the foundation for an atlas of transcriptomic cell biology.

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

DOI
10.1038/s41586-018-0590-4

Identification and characterization of ubiquitinylation sites in TAR DNA-binding protein of 43 kDa (TDP-43)

NOMIS Researcher(s)

Published in

October 12, 2018

TAR DNA-binding protein of 43 kDa (TDP-43) forms pathological aggregates in neurodegenerative diseases, particularly in certain forms of frontotemporal dementia and amyotrophic lateral sclerosis. Pathological modifications of TDP-43 include proteolytic fragmentation, phosphorylation, and ubiquitinylation. A pathognomonic TDP-43 C-terminal fragment (CTF) spanning amino acids 193– 414 contains only four lysine residues that could be potentially ubiquitinylated. Here, serial mutagenesis of these four lysines to arginine revealed that not a single residue is responsible for the ubiquitinylation of mCherry-tagged CTF. Removal of all four lysines was necessary to suppress ubiquitinylation. Interestingly, Lys-408 substitution enhanced the pathological phosphorylation of the immediately adjacent serine residues 409/410 in the context of mCherry-CTF. Thus, Lys-408 ubiquitinylation appears to hinder Ser-409/ 410 phosphorylation in TDP-43 CTF. However, we did not observe the same effect for full-length TDP-43. We extended the mutagenesis study to full-length TDP-43 and performed MS. Ubiquitinylated lysine residues were identified in the nuclear localization sequence (NLS; Lys-84 and Lys-95) and RNA-binding region (mostly Lys-160, Lys-181, and Lys-263). Mutagenesis of Lys-84 confirmed its importance as the major determinant for nuclear import, whereas Lys-95 mutagenesis did not significantly affect TDP-43’s nucleo-cytoplasmic distribution, solubility, aggregation, and RNA-processing activities. Nevertheless, the K95A mutant had significantly reduced Ser-409/410 phosphorylation, emphasizing the suspected interplay between TDP-43 ubiquitinylation and phosphorylation. Collectively, our analysis of TDP-43 ubiquitinylation sites indicates that the NLS residues Lys-84 and Lys-95 have more prominent roles in TDP-43 function than the more C-terminal lysines and suggests a link between specific ubiquitinylation events and pathological TDP-43 phosphorylation.

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

DOI
10.1074/jbc.RA118.003440

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

NOMIS Researcher(s)

Published in

October 1, 2018

Objective: The basis for clinical variation related to underlying progressive supranuclear palsy (PSP) pathology is unknown. We performed a genome-wide association study (GWAS) to identify genetic determinants of PSP phenotype. Methods: Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson syndrome (RS) and non-RS groups. We carried out separate logistic regression GWASs to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS = 367, non-RS = 130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/coexpression patterns of our identified genes and used our data to carry out gene-based association testing. Results: Our lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome-wide significance in our whole cohort analysis (odds ratio = 5.5, 95% confidence interval = 3.2–10.0, p = 1.7 × 10−9). rs564309 is an intronic variant of the tripartite motif-containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene-based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia. Interpretation: Our study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease-modifying therapies. Ann Neurol 2018;84:485–496.

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

DOI
10.1002/ana.25308

Cooperative Metabolic Adaptations in the Host Can Favor Asymptomatic Infection and Select for Attenuated Virulence in an Enteric Pathogen

NOMIS Researcher(s)

Published in

September 20, 2018

Pathogen virulence exists on a continuum. The strategies that drive symptomatic or asymptomatic infections remain largely unknown. We took advantage of the concept of lethal dose 50 (LD50) to ask which component of individual non-genetic variation between hosts defines whether they survive or succumb to infection. Using the enteric pathogen Citrobacter, we found no difference in pathogen burdens between healthy and symptomatic populations. Iron metabolism-related genes were induced in asymptomatic hosts compared to symptomatic or naive mice. Dietary iron conferred complete protection without influencing pathogen burdens, even at 1000× the lethal dose of Citrobacter. Dietary iron induced insulin resistance, increasing glucose levels in the intestine that were necessary and sufficient to suppress pathogen virulence. A short course of dietary iron drove the selection of attenuated Citrobacter strains that can transmit and asymptomatically colonize naive hosts, demonstrating that environmental factors and cooperative metabolic strategies can drive conversion of pathogens toward commensalism. Defense strategies that are cooperative rather than antagonistic can promote asymptomatic infection and select for reduced virulence in a bacterial pathogen.

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

DOI
10.1016/j.cell.2018.07.016

Glioblastoma treatments: An account of recent industrial developments

NOMIS Researcher(s)

Published in

September 13, 2018

The different drugs and medical devices, which are commercialized or under industrial development for glioblastoma treatment, are reviewed. Their different modes of action are analyzed with a distinction being made between the effects of radiation, the targeting of specific parts of glioma cells, and immunotherapy. Most of them are still at a too early stage of development to firmly conclude about their efficacy. Optune, which triggers antitumor activity by blocking the mitosis of glioma cells under the application of an alternating electric field, seems to be the only recently developed therapy with some efficacy reported on a large number of GBM patients. The need for early GBM diagnosis is emphasized since it could enable the treatment of GBM tumors of small sizes, possibly easier to eradicate than larger tumors. Ways to improve clinical protocols by strengthening preclinical studies using of a broader range of different animal and tumor models are also underlined. Issues related with efficient drug delivery and crossing of blood brain barrier are discussed. Finally societal and economic aspects are described with a presentation of the orphan drug status that can accelerate the development of GBM therapies, patents protecting various GBM treatments, the different actors tackling GBM disease, the cost of GBM treatments, GBM market figures, and a financial analysis of the different companies involved in the development of GBM therapies.

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

DOI
10.3389/fphar.2018.00879

Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice

NOMIS Researcher(s)

Published in

September 4, 2018

Background: Heterozygous loss-of-function mutations in the progranulin gene (GRN) lead to frontotemporal lobar degeneration (FTLD) while the complete loss of progranulin (PGRN) function results in neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Thus the growth factor-like protein PGRN may play an important role in lysosomal degradation. In line with a potential lysosomal function, PGRN is partially localized and processed in lysosomes. In the central nervous system (CNS), PGRN is like other lysosomal proteins highly expressed in microglia, further supporting an important role in protein degradation. We have previously reported that cathepsin (Cat) D is elevated in GRN-associated FTLD patients and Grn knockout mice. However, the primary mechanism that causes impaired protein degradation and elevated CatD levels upon PGRN deficiency in NCL and FTLD remains unclear. Methods: mRNA expression analysis of selected lysosomal hydrolases, lysosomal membrane proteins and autophagy-related genes was performed by NanoString nCounter panel. Protein expression, maturation and in vitro activity of Cat D, B and L in mouse embryonic fibroblasts (MEF) and brains of Grn knockout mice were investigated. To selectively characterize microglial and non-microglial brain cells, an acutely isolated microglia fraction using MACS microbeads (Miltenyi Biotec) conjugated with CD11b antibody and a microglia-depleted fraction were analyzed for protein expression and maturation of selected cathepsins. Results: We demonstrate that loss of PGRN results in enhanced expression, maturation and in vitro activity of Cat D, B and L in mouse embryonic fibroblasts and brain extracts of aged Grn knockout mice. Consistent with an overall enhanced expression and activity of lysosomal proteases in brain of Grn knockout mice, we observed an age-dependent transcriptional upregulation of certain lysosomal proteases. Thus, lysosomal dysfunction is not reflected by transcriptional downregulation of lysosomal proteases but rather by the upregulation of certain lysosomal proteases in an age-dependent manner. Surprisingly, cell specific analyses identified early lysosomal deficits in microglia before enhanced cathepsin levels could be detected in other brain cells, suggesting different functional consequences on lysosomal homeostasis in microglia and other brain cells upon lack of PGRN. Conclusions: The present study uncovers early and selective lysosomal dysfunctions in Grn knockout microglia/macrophages. Dysregulated lysosomal homeostasis in microglia might trigger compensatory lysosomal changes in other brain cells.

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

DOI
10.1186/s13024-018-0281-5

Novel antibodies reveal presynaptic localization of C9orf72 protein and reduced protein levels in C9orf72 mutation carriers

NOMIS Researcher(s)

Published in

August 3, 2018

Hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, but the pathogenic mechanism of this mutation remains unresolved. Haploinsufficiency has been proposed as one potential mechanism. However, insights if and how reduced C9orf72 proteins levels might contribute to disease pathogenesis are still limited because C9orf72 expression, localization and functions in the central nervous system (CNS) are uncertain, in part due to the poor specificity of currently available C9orf72 antibodies.Here, we generated and characterized novel knock-out validated monoclonal rat and mouse antibodies against C9orf72. We found that C9orf72 is a low abundant, cytoplasmic, highly soluble protein with the long 481 amino acid isoform being the predominant, if not exclusively, expressed protein isoform in mouse tissues and human brain. As consequence of the C9orf72 repeat expansion, C9orf72 protein levels in the cerebellum were reduced to 80% in our series of C9orf72 mutation carriers (n = 17) compared to controls (n = 26). However, no associations between cerebellar protein levels and clinical phenotypes were seen. Finally, by utilizing complementary immunohistochemical and biochemical approaches including analysis of human iPSC derived motor neurons, we identified C9orf72, in addition to its association to lysosomes, to be localized to the presynapses and able to interact with all members of the RAB3 protein family, suggestive of a role for C9orf72 in regulating synaptic vesicle functions by potentially acting as guanine nucleotide exchange factor for RAB3 proteins.In conclusion, our findings provide further evidence for haploinsufficiency as potential mechanism in C9orf72 pathogenesis by demonstrating reduced protein levels in C9orf72 mutation carriers and important novel insights into the physiological role of C9orf72 in the CNS. Moreover, the described novel monoclonal C9orf72 antibodies will be useful tools to further dissect the cellular and molecular functions of C9orf72.

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

DOI
10.1186/s40478-018-0579-0

Non-political anger shifts political preferences towards stronger leaders

NOMIS Researcher(s)

Published in

August 1, 2018

Past research has shown that anger is associated with support for confrontational and punitive responses during crises, and notably with the endorsement of authoritarian ideologies. One important question is whether it is anger generated specifically in a political context that explains the association between anger and specific political preferences or whether any feeling of anger would be associated with changes in political attitudes. Here, we tested the effect of non-politically motivated incidental anger on the preference for strong leaders. In line with past research, we predicted that anger would increase preferences for strong leaders. Across two experiments, we exposed participants to an anger induction task. Before and after this experimental manipulation, we measured participants’ political leader preferences by asking them to choose between the faces of two leaders they would vote for in a hypothetical election. The level of self-reported anger predicted the probability of choosing more dominant-looking and less trustworthy-looking leaders after the induction, suggesting that even non-political incidental anger increases preferences for strong leaders.

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

DOI
10.1038/s41598-022-15765-8

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