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Publications in Biomedical Research by NOMIS researchers

A neuronal blood marker is associated with mortality in old age

NOMIS Researcher(s)

Published in

February 1, 2021

Neurofilament light chain (NfL) has emerged as a promising blood biomarker for the progression of various neurological diseases. NfL is a structural protein of nerve cells, and elevated NfL levels in blood are thought to mirror damage to the nervous system. We find that plasma NfL levels increase in humans with age (n = 122; 21–107 years of age) and correlate with changes in other plasma proteins linked to neural pathways. In centenarians (n = 135), plasma NfL levels are associated with mortality equally or better than previously described multi-item scales of cognitive or physical functioning, and this observation was replicated in an independent cohort of nonagenarians (n = 180). Plasma NfL levels also increase in aging mice (n = 114; 2–30 months of age), and dietary restriction, a paradigm that extends lifespan in mice, attenuates the age-related increase in plasma NfL levels. These observations suggest a contribution of nervous system functional deterioration to late-life mortality.

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

DOI
10.1038/s43587-021-00028-4

Asynchronous, contagious and digital aging

NOMIS Researcher(s)

Published in

January 1, 2021

Organismal aging is often characterized as a steady, monotonic decline of organ and tissue function. However, recent studies indicate spatial and temporal variations of aging rates across the lifespan. We consider these variations from the perspective of underlying cellular changes. Cells in certain tissues may age earlier and produce signals that accelerate the aging of other cells, locally or distantly, acting as drivers for organismal aging and leading to a lack of synchronous aging between tissues. As cells adopt new homeostatic states, cellular aging can be viewed, at least in part, as a quantal process we refer to as digital aging. Analog declines of tissue function with age may be the sum of underlying digital events. Cellular aging, digital or otherwise, is not uniform across time or space within organisms or between organisms of the same species. Advanced systems-level and single-cell methodologies will refine our understanding of cell and tissue aging, and how these processes integrate to produce the complexities of individual, organismal aging.

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

DOI
10.1038/s43587-020-00015-1

Impact of tspo receptor polymorphism on [18 f]ge-180 binding in healthy brain and pseudo-reference regions of neurooncological and neurodegenerative disorders

NOMIS Researcher(s)

Published in

January 1, 2021

TSPO-PET tracers are sensitive to a single-nucleotide polymorphism (rs6971-SNP), resulting in low-, medium-and high-affinity binders (LABs, MABs and HABS), but the clinical relevance of [18 F]GE-180 is still unclear. We evaluated the impact of rs6971-SNP on in vivo [18 F]GE-180 binding in a healthy brain and in pseudo-reference tissue in neuro-oncological and neurodegenerative diseases. Standardized uptake values (SUVs) of [18 F]GE-180-PET were assessed using a manually drawn region of interest in the frontoparietal and cerebellar hemispheres. The SUVs were compared between the LABs, MABs and HABs in control, glioma, four-repeat tauopathy (4RT) and Alzheimer’s disease (AD) subjects. Second, the SUVs were compared between the patients and controls within their rs6971-subgroups. After excluding patients with prior therapy, 24 LABs (7 control, 5 glioma, 6 4RT and 6 AD) were analyzed. Age-and sex-matched MABs (n = 38) and HABs (n = 50) were selected. The LABs had lower frontoparietal and cerebellar SUVs when compared with the MABs and HABs, but no significant difference was observed between the MABs and HABs. Within each rs6971 group, no SUV difference between the patients and controls was detected in the pseudo-reference tissues. The rs6971-SNP affects [18 F]GE-180 quantification, revealing lower binding in the LABs when compared to the MABs and HABs. The frontoparietal and cerebellar ROIs were successfully validated as pseudo-reference regions.

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

DOI
10.3390/life11060484

FUS-dependent liquid-liquid phase separation is important for DNA repair initiation

NOMIS Researcher(s)

Published in

January 1, 2021

RNA-binding proteins (RBPs) are emerging as important effectors of the cellular DNA damage response (DDR). The RBP FUS is implicated in RNA metabolism and DNA repair, and it undergoes reversible liquid-liquid phase separation (LLPS) in vitro. Here, we demonstrate that FUS-dependent LLPS is necessary for the initiation of the DDR. Using laser microirradiation in FUS-knockout cells, we show that FUS is required for the recruitment to DNA damage sites of the DDR factors KU80, NBS1, and 53BP1 and of SFPQ, another RBP implicated in the DDR. The relocation of KU80, NBS1, and SFPQ is similarly impaired by LLPS inhibitors, or LLPS-deficient FUS variants. We also show that LLPS is necessary for efficient γH2AX foci formation. Finally, using superresolution structured illumination microscopy, we demonstrate that the absence of FUS impairs the proper arrangement of γH2AX nanofoci into higher-order clusters. These findings demonstrate the early requirement for FUS-dependent LLPS in the activation of the DDR and the proper assembly of DSB repair complexes.

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

DOI
10.1083/JCB.202008030

A Molecular Calcium Integrator Reveals a Striatal Cell Type Driving Aversion

NOMIS Researcher(s)

Published in

December 23, 2020

The ability to record transient cellular events in the DNA or RNA of cells would enable precise, large-scale analysis, selection, and reprogramming of heterogeneous cell populations. Here, we report a molecular technology for stable genetic tagging of cells that exhibit activity-related increases in intracellular calcium concentration (FLiCRE). We used FLiCRE to transcriptionally label activated neural ensembles in the nucleus accumbens of the mouse brain during brief stimulation of aversive inputs. Using single-cell RNA sequencing, we detected FLiCRE transcripts among the endogenous transcriptome, providing simultaneous readout of both cell-type and calcium activation history. We identified a cell type in the nucleus accumbens activated downstream of long-range excitatory projections. Taking advantage of FLiCRE’s modular design, we expressed an optogenetic channel selectively in this cell type and showed that direct recruitment of this otherwise genetically inaccessible population elicits behavioral aversion. The specificity and minute resolution of FLiCRE enables molecularly informed characterization, manipulation, and reprogramming of activated cellular ensembles.

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

DOI
10.1016/j.cell.2020.11.015

Nuclear Import Receptors Directly Bind to Arginine-Rich Dipeptide Repeat Proteins and Suppress Their Pathological Interactions

NOMIS Researcher(s)

Published in

December 22, 2020

Hutten et al. show that arginine-rich dipeptide repeat proteins (DPRs) associated with the neurodegenerative diseases ALS and FTD bind directly to importins, promote their condensation, and interfere with importin function. Elevated importin levels can shield arginine-rich DPRs and suppress DPR-induced phase separation of TDP-43 and RNA.

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

DOI
10.1016/j.celrep.2020.108538

Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair

NOMIS Researcher(s)

Published in

December 1, 2020

Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification.

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

DOI
10.1038/s41467-020-15845-1

Drops and fibers – How biomolecular condensates and cytoskeletal filaments influence each other

NOMIS Researcher(s)

Published in

December 1, 2020

The cellular cytoskeleton self-organizes by specific monomer-monomer interactions resulting in the polymerization of filaments. While we have long thought about the role of polymerization in cytoskeleton formation, we have only begun to consider the role of condensation in cytoskeletal organization. In this review, we highlight how the interplay between polymerization and condensation leads to the formation of the cytoskeleton.

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

DOI
10.1042/ETLS20190174

Structural determinants and their role in cyanobacterial morphogenesis

NOMIS Researcher(s)

Published in

December 1, 2020

Cells have to erect and sustain an organized and dynamically adaptable structure for an efficient mode of operation that allows drastic morphological changes during cell growth and cell division. These manifold tasks are complied by the so-called cytoskeleton and its associated proteins. In bacteria, FtsZ and MreB, the bacterial homologs to tubulin and actin, respectively, as well as coiled-coil-rich proteins of intermediate filament (IF)-like function to fulfil these tasks. Despite generally being characterized as Gram-negative, cyanobacteria have a remarkably thick peptidoglycan layer and possess Gram-positive-specific cell division proteins such as SepF and DivIVA-like proteins, besides Gram-negative and cyanobacterial-specific cell division proteins like MinE, SepI, ZipN (Ftn2) and ZipS (Ftn6). The diversity of cellular morphologies and cell growth strategies in cyanobacteria could therefore be the result of additional unidentified structural determinants such as cytoskeletal proteins. In this article, we review the current advances in the understanding of the cyanobacterial cell shape, cell division and cell growth.

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

DOI
10.3390/life10120355

Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis

NOMIS Researcher(s)

Published in

December 1, 2020

Mutations in the RNA-binding protein Fused in Sarcoma (FUS) cause early-onset amyotrophic lateral sclerosis (ALS). However, a detailed understanding of central RNA targets of FUS and their implications for disease remain elusive. Here, we use a unique blend of crosslinking and immunoprecipitation (CLIP) and NMR spectroscopy to identify and characterise physiological and pathological RNA targets of FUS. We find that U1 snRNA is the primary RNA target of FUS via its interaction with stem-loop 3 and provide atomic details of this RNA-mediated mode of interaction with the U1 snRNP. Furthermore, we show that ALS-associated FUS aberrantly contacts U1 snRNA at the Sm site with its zinc finger and traps snRNP biogenesis intermediates in human and murine motor neurons. Altogether, we present molecular insights into a FUS toxic gain-of-function involving direct and aberrant RNA-binding and strengthen the link between two motor neuron diseases, ALS and spinal muscular atrophy (SMA).

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

DOI
10.1038/s41467-020-20191-3

The major genetic risk factor for severe COVID-19 is inherited from Neanderthals

NOMIS Researcher(s)

Published in

November 26, 2020

A recent genetic association study1 identified a gene cluster on chromosome 3 as a risk locus for respiratory failure after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A separate study (COVID-19 Host Genetics Initiative)2 comprising 3,199 hospitalized patients with coronavirus disease 2019 (COVID-19) and control individuals showed that this cluster is the major genetic risk factor for severe symptoms after SARS-CoV-2 infection and hospitalization. Here we show that the risk is conferred by a genomic segment of around 50 kilobases in size that is inherited from Neanderthals and is carried by around 50% of people in south Asia and around 16% of people in Europe.

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

DOI
10.1038/s41586-020-2818-3

Patterns and Drivers of Extracellular Enzyme Activity in New Zealand Glacier-Fed Streams

NOMIS Researcher(s)

Published in

November 19, 2020

Glacier-fed streams (GFSs) exhibit near-freezing temperatures, variable flows, and often high turbidities. Currently, the rapid shrinkage of mountain glaciers is altering the delivery of meltwater, solutes, and particulate matter to GFSs, with unknown consequences for their ecology. Benthic biofilms dominate microbial life in GFSs, and play a major role in their biogeochemical cycling. Mineralization is likely an important process for microbes to meet elemental budgets in these systems due to commonly oligotrophic conditions, and extracellular enzymes retained within the biofilm enable the degradation of organic matter and acquisition of carbon (C), nitrogen (N), and phosphorus (P). The measurement and comparison of these extracellular enzyme activities (EEA) can in turn provide insight into microbial elemental acquisition effort relative to environmental availability. To better understand how benthic biofilm communities meet resource demands, and how this might shift as glaciers vanish under climate change, we investigated biofilm EEA in 20 GFSs varying in glacier influence from New Zealand’s Southern Alps. Using turbidity and distance to the glacier snout normalized for glacier size as proxies for glacier influence, we found that bacterial abundance (BA), chlorophyll a (Chl a), extracellular polymeric substances (EPS), and total EEA per gram of sediment increased with decreasing glacier influence. Yet, when normalized by BA, EPS decreased with decreasing glacier influence, Chl a still increased, and there was no relationship with total EEA. Based on EEA ratios, we found that the majority of GFS microbial communities were N-limited, with a few streams of different underlying bedrock geology exhibiting P-limitation. Cell-specific C-acquiring EEA was positively related to the ratio of Chl a to BA, presumably reflecting the utilization of algal exudates. Meanwhile, cell-specific N-acquiring EEA were positively correlated with the concentration of dissolved inorganic nitrogen (DIN), and both N- and P-acquiring EEA increased with greater cell-specific EPS. Overall, our results reveal greater glacier influence to be negatively related to GFS biofilm biomass parameters, and generally associated with greater microbial N demand. These results help to illuminate the ecology of GFS biofilms, along with their biogeochemical response to a shifting habitat template with ongoing climate change.

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

DOI
10.3389/fmicb.2020.591465

Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging

NOMIS Researcher(s)

Published in

November 1, 2020

We previously identified 529 proteins that had been reported by multiple different studies to change their expression level with age in human plasma. In the present study, we measured the q-value and age coefficient of these proteins in a plasma proteomic dataset derived from 4263 individuals. A bioinformatics enrichment analysis of proteins that significantly trend toward increased expression with age strongly implicated diverse inflammatory processes. A literature search revealed that at least 64 of these 529 proteins are capable of regulating life span in an animal model. Nine of these proteins (AKT2, GDF11, GDF15, GHR, NAMPT, PAPPA, PLAU, PTEN, and SHC1) significantly extend life span when manipulated in mice or fish. By performing machine-learning modeling in a plasma proteomic dataset derived from 3301 individuals, we discover an ultra-predictive aging clock comprised of 491 protein entries. The Pearson correlation for this clock was 0.98 in the learning set and 0.96 in the test set while the median absolute error was 1.84 years in the learning set and 2.44 years in the test set. Using this clock, we demonstrate that aerobic-exercised trained individuals have a younger predicted age than physically sedentary subjects. By testing clocks associated with 1565 different Reactome pathways, we also show that proteins associated with signal transduction or the immune system are especially capable of predicting human age. We additionally generate a multitude of age predictors that reflect different aspects of aging. For example, a clock comprised of proteins that regulate life span in animal models accurately predicts age.

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

DOI
10.1111/acel.13256

Shifts and drifts in prion science

NOMIS Researcher(s)

Published in

October 2, 2020

null

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

DOI
10.1126/science.abb8577

Network Engineering Using Autonomous Agents Increases Cooperation in Human Groups

NOMIS Researcher(s)

Published in

September 25, 2020

Cooperation in human groups is challenging, and various mechanisms are required to sustain it, although it nevertheless usually decays over time. Here, we perform theoretically informed experiments involving networks of humans (1,024 subjects in 64 networks) playing a public-goods game to which we sometimes added autonomous agents (bots) programmed to use only local knowledge. We show that cooperation can not only be stabilized, but even promoted, when the bots intervene in the partner selections made by the humans, re-shaping social connections locally within a larger group. Cooperation rates increased from 60.4% at baseline to 79.4% at the end. This network-intervention strategy outperformed other strategies, such as adding bots playing tit-for-tat. We also confirm that even a single bot can foster cooperation in human groups by using a mixed strategy designed to support the development of cooperative clusters. Simple artificial intelligence can increase the cooperation of groups.

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

DOI
10.1016/j.isci.2020.101438

Protective anti-prion antibodies in human immunoglobulin repertoires

NOMIS Researcher(s)

Published in

September 7, 2020

Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here, we identified > 6,000 PrP-binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage-derived antibodies. When expressed recombinantly, these antibodies exhibited anti-PrP reactivity. Furthermore, we surveyed 48,718 samples from 37,894 hospital patients for the presence of anti-PrP IgGs and found 21 high-titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti-PrP autoimmunity is innocuous. The existence of anti-prion antibodies in unbiased human immunological repertoires suggests that they might clear nascent prions early in life. Combined with the reported lack of such antibodies in carriers of disease-associated PRNP mutations, this suggests a link to the low incidence of spontaneous prion diseases in human populations.

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

DOI
10.15252/emmm.202012739

A Neanderthal Sodium Channel Increases Pain Sensitivity in Present-Day Humans

NOMIS Researcher(s)

Published in

September 7, 2020

The sodium channel Nav1.7 is crucial for impulse generation and conduction in peripheral pain pathways [1]. In Neanderthals, the Nav1.7 protein carried three amino acid substitutions (M932L, V991L, and D1908G) relative to modern humans. We expressed Nav1.7 proteins carrying all combinations of these substitutions and studied their electrophysiological effects. Whereas the single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying all three substitutions, as well as the combination of V991L with D1908G, shows reduced inactivation, suggesting that peripheral nerves were more sensitive to painful stimuli in Neanderthals than in modern humans. We show that, due to gene flow from Neanderthals, the three Neanderthal substitutions are found in ∼0.4% of present-day Britons, where they are associated with heightened pain sensitivity.

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

DOI
10.1016/j.cub.2020.06.045

Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and hutchinson-gilford progeria syndrome

NOMIS Researcher(s)

Published in

September 1, 2020

Vascular dysfunctions are a common feature of multiple age-related diseases. However, modeling healthy and pathological aging of the human vasculature represents an unresolved experimental challenge. Here, we generated induced vascular endothelial cells (iVECs) and smooth muscle cells (iSMCs) by direct reprogramming of healthy human fibroblasts from donors of different ages and Hutchinson-Gilford Progeria Syndrome (HGPS) patients. iVECs induced from old donors revealed upregulation of GSTM1 and PALD1, genes linked to oxidative stress, inflammation and endothelial junction stability, as vascular aging markers. A functional assay performed on PALD1 KD VECs demonstrated a recovery in vascular permeability. We found that iSMCs from HGPS donors overexpressed bone morphogenetic protein (BMP) 4, which plays a key role in both vascular calcification and endothelial barrier damage observed in HGPS. Strikingly, BMP4 concentrations are higher in serum from HGPS vs. age-matched mice. Furthermore, targeting BMP4 with blocking antibody recovered the functionality of the vascular barrier in vitro, hence representing a potential future therapeutic strategy to limit cardiovascular dysfunction in HGPS. These results show that iVECs and iSMCs retain disease-related signatures, allowing modeling of vascular aging and HGPS in vitro.

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

DOI
10.7554/ELIFE.54383

Ribosomal profiling during prion disease uncovers progressive translational derangement in glia but not in neurons

NOMIS Researcher(s)

Published in

September 1, 2020

Prion diseases are caused by PrPSc, a self-replicating pathologically misfolded protein that exerts toxicity predominantly in the brain. The administration of PrPSc causes a robust, reproducible and specific disease manifestation. Here, we have applied a combination of translating ribosome affinity purification and ribosome profiling to identify biologically relevant prion-induced changes during disease progression in a cell-type-specific and genome-wide manner. Terminally diseased mice with severe neurological symptoms showed extensive alterations in astrocytes and microglia. Surprisingly, we detected only minor changes in the translational profiles of neurons. Prion-induced alterations in glia overlapped with those identified in other neurodegenerative diseases, suggesting that similar events occur in a broad spectrum of pathologies. Our results suggest that aberrant translation within glia may suffice to cause severe neurological symptoms and may even be the primary driver of prion disease.

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

DOI
10.7554/ELIFE.62911

Controlled Cycling and Quiescence Enables Efficient HDR in Engraftment-Enriched Adult Hematopoietic Stem and Progenitor Cells

NOMIS Researcher(s)

Published in

September 1, 2020

Genome editing often takes the form of either error-prone sequence disruption by non-homologous end joining (NHEJ) or sequence replacement by homology-directed repair (HDR). Although NHEJ is generally effective, HDR is often difficult in primary cells. Here, we use a combination of immunophenotyping, next-generation sequencing, and single-cell RNA sequencing to investigate and reprogram genome editing outcomes in subpopulations of adult hematopoietic stem and progenitor cells. We find that although quiescent stem-enriched cells mostly use NHEJ, non-quiescent cells with the same immunophenotype use both NHEJ and HDR. Inducing quiescence before editing results in a loss of HDR in all cell subtypes. We develop a strategy of controlled cycling and quiescence that yields a 6-fold increase in the HDR/NHEJ ratio in quiescent stem cells ex vivo and in vivo. Our results highlight the tension between editing and cellular physiology and suggest strategies to manipulate quiescent cells for research and therapeutic genome editing. Shin et al. find that quiescent blood stem cells only perform error-prone NHEJ to repair double-strand breaks, whereas cycling blood stem cells perform both error-prone NHEJ and precise HDR. They show that inducing quiescence after a short period of cycling yields blood stem cells harboring high levels of HDR.

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

DOI
10.1016/j.celrep.2020.108093

Architecture and function of human uromodulin filaments in urinary tract infections

NOMIS Researcher(s)

Published in

August 21, 2020

Uromodulin is the most abundant protein in human urine, and it forms filaments that antagonize the adhesion of uropathogens; however, the filament structure and mechanism of protection remain poorly understood. We used cryo–electron tomography to show that the uromodulin filament consists of a zigzag-shaped backbone with laterally protruding arms. N-glycosylation mapping and biophysical assays revealed that uromodulin acts as a multivalent ligand for the bacterial type 1 pilus adhesin, presenting specific epitopes on the regularly spaced arms. Imaging of uromodulin-uropathogen interactions in vitro and in patient urine showed that uromodulin filaments associate with uropathogens and mediate bacterial aggregation, which likely prevents adhesion and allows clearance by micturition. These results provide a framework for understanding uromodulin in urinary tract infections and in its more enigmatic roles in physiology and disease.

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

DOI
10.1126/science.aaz9866

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