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Publications in Health Sciences by NOMIS researchers

Novel regulators of PrPC biosynthesis revealed by genome-wide RNA interference

NOMIS Researcher(s)

Published in

October 1, 2021

The cellular prion protein PrPC is necessary for prion replication, and its reduction greatly increases life expectancy in animal models of prion infection. Hence the factors controlling the levels of PrPC may represent therapeutic targets against human prion diseases. Here we performed an arrayed whole-transcriptome RNA interference screen to identify modulators of PrPC expression. We cultured human U251-MG glioblastoma cells in the presence of 64’752 unique siRNAs targeting 21’584 annotated human genes, and measured PrPC using a one-pot fluorescence-resonance energy transfer immunoassay in 51’128 individual micro-plate wells. This screen yielded 743 candidate regulators of PrPC. When downregulated, 563 of these candidates reduced and 180 enhanced PrPC expression. Recursive candidate attrition through multiple secondary screens yielded 54 novel regulators of PrPC, 9 of which were confirmed by CRISPR interference as robust regulators of PrPC biosynthesis and degradation. The phenotypes of 6 of the 9 candidates were inverted in response to transcriptional activation using CRISPRa. The RNA-binding post-transcriptional repressor Pumilio-1 was identified as a potent limiter of PrPC expression through the degradation of PRNP mRNA. Because of its hypothesis-free design, this comprehensive genetic-perturbation screen delivers an unbiased landscape of the genes regulating PrPC levels in cells, most of which were unanticipated, and some of which may be amenable to pharmacological targeting in the context of antiprion therapies.

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

DOI
10.1371/journal.ppat.1010013

The porphyrin TMPyP4 inhibits elongation during the noncanonical translation of the FTLD/ALS-associated GGGGCC repeat in the C9orf72 gene

NOMIS Researcher(s)

Published in

October 1, 2021

GGGGCC (G4C2) repeat expansion in the C9orf72 gene has been shown to cause frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Dipeptide repeat proteins produced through repeat-associated non-AUG (RAN) translation are recognized as potential drivers for neurodegeneration. Therefore, selective inhibition of RAN translation could be a therapeutic avenue to treat these neurodegenerative diseases. It was previously known that the porphyrin TMPyP4 binds to G4C2 repeat RNA. However, the consequences of this interaction have not been well characterized. Here, we confirmed that TMPyP4 inhibits C9orf72 G4C2 repeat translation in cellular and in in vitro translation systems. An artificial insertion of an AUG codon failed to cancel the translation inhibition, suggesting that TMPyP4 acts downstream of non-AUG translation initiation. Polysome profiling assays also revealed polysome retention on G4C2 repeat RNA, along with inhibition of translation, indicating that elongating ribosomes stall on G4C2 repeat RNA. Urea-resistant interaction between G4C2 repeat RNA and TMPyP4 likely contributes to this ribosome stalling and thus to selective inhibition of RAN translation. Taken together, our data reveal a novel mode of action of TMPyP4 as an inhibitor of G4C2 repeat translation elongation.

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

DOI
10.1016/j.jbc.2021.101120

Helping the waiter to hold his tray: Rigid haptic linkage promotes inter-personal motor coordination

NOMIS Researcher(s)

Published in

October 1, 2021

When a glass is lifted from a tray, there is a challenge for the waiter. He must quickly compensate for the reduction in the weight of the tray to keep it balanced. This compensation is easily achieved if the waiter lifts the glass himself. Because he has, himself, initiated the action, he can predict the timing and the magnitude of the perturbation of the tray and respond (via the holding hand) accordingly. In this study, we examined coordination when either one or two people hold the tray while either one of them or a third person removes the glass. Our results show that there is exquisite coordination between the two people holding the tray. We suggest that this coordination depends upon the haptic link provided by the rigid platform that both people are holding. We conclude that the guest at a reception should not lift his drink from the waiter’s tray until they have the waiter’s attention but, if too thirsty to wait, should lend a hand holding the tray.

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

DOI
10.1177/17470218211009082

The Polar Legionella Icm/Dot T4SS Establishes Distinct Contact Sites with the Pathogen Vacuole Membrane

NOMIS Researcher(s)

Published in

October 1, 2021

Legionella pneumophila, the causative agent of Legionnaires’ disease, is a facultative intracellular pathogen that survives inside phagocytic host cells by establishing a protected replication niche, termed the “Legionella-containing vacuole” (LCV). To form an LCV and subvert pivotal host pathways, L. pneumophila employs a type IV secretion system (T4SS), which translocates more than 300 different effector proteins into the host cell. The L. pneumophila T4SS complex has been shown to span the bacterial cell envelope at the bacterial poles. However, the interactions between the T4SS and the LCV membrane are not understood. Using cryo-focused ion beam milling, cryo-electron tomography, and confocal laser scanning fluorescence microscopy, we show that up to half of the intravacuolar L. pneumophila bacteria tether their cell pole to the LCV membrane. Tethering coincides with the presence and function of T4SSs and likely promotes the establishment of distinct contact sites between T4SSs and the LCV membrane. Contact sites are characterized by indentations in the limiting LCV membrane and localize juxtaposed to T4SS machineries. The data are in agreement with the notion that effector translocation occurs by close membrane contact rather than by an extended pilus. Our findings provide novel insights into the interactions of the L. pneumophila T4SS with the LCV membrane in situ. IMPORTANCE Legionnaires’ disease is a life-threatening pneumonia, which is characterized by high fever, coughing, shortness of breath, muscle pain, and headache. The disease is caused by the amoeba-resistant bacterium L. pneumophila found in various soil and aquatic environments and is transmitted to humans via the inhalation of small bacteria-containing droplets. An essential virulence factor of L. pneumophila is a so-called “type IV secretion system” (T4SS), which, by injecting a plethora of “effector proteins” into the host cell, determines pathogen-host interactions and the formation of a distinct intracellular compartment, the “Legionella-containing vacuole” (LCV). It is unknown how the T4SS makes contact to the LCV membrane to deliver the effectors. In this study, we identify indentations in the host cell membrane in close proximity to functional T4SSs localizing at the bacterial poles. Our work reveals first insights into the architecture of Legionella-LCV contact sites.

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

DOI
10.1128/mBio.02180-21

How do we relate to our heart? Neurobehavioral differences across three types of engagement with cardiac interoception

NOMIS Researcher(s)

Published in

October 1, 2021

Standard measures of interoception are typically limited to the conscious perception of heartbeats. However, the fundamental purpose of interoceptive signaling, is to regulate the body. We present a novel biofeedback paradigm to explore the neurobehavioral consequences of three different types of engagement with cardiac interoception (Attend, Feel, Regulate) while participants perform a ‘cardiac recognition’ task. For both the Feel and Regulate conditions, participants displayed enhanced recognition of their own heartbeat, accompanied by larger heartbeat-evoked potentials (HEPs), suggesting that these approaches could be used interchangeably. Importantly, meta-cognitive interoceptive insight was highest in the Regulate condition, indicative of stronger engagement with interoceptive signals in addition to greater ecological validity. Only in the passive interoception condition (Feel) was a significant association found between accuracy in recognising one’s own heartbeat and the amplitude of HEPs. Overall, our results imply that active conditions have an important role to play in future investigation of interoception.

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

DOI
10.1016/j.biopsycho.2021.108198

Loss of PIKfyve drives the spongiform degeneration in prion diseases

NOMIS Researcher(s)

Published in

September 7, 2021

Brain-matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion-mimetic antibodies deplete the phosphoinositide kinase PIKfyve—which controls endolysosomal maturation—from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt-Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB-dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion-infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P2 suppressed prion-induced vacuolation and restored lysosomal homeostasis. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.

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

DOI
10.15252/emmm.202114714

LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies

NOMIS Researcher(s)

Published in

September 7, 2021

While the initial pathology of Parkinson’s disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid.

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

DOI
10.15252/emmm.202114745

Counting on you: How mhc tetramers revolutionized the study of t cell memory and cd81 t cell exhaustion

NOMIS Researcher(s)

Published in

September 1, 2021

Fundamental to the concept of adaptive immunity is the ability of lymphocytes to recognize and respond to specific foreign Ags. B and T cells that are specific for peptides of an invading pathogen will proliferate and produce Abs, cytokines, and effector molecules and, upon resolution of the infection, form a long-lived memory response to protect against reinfection. However, for many decades, it was not possible for immunologists to track cells specific to a particular Ag over an extended time period. And although we have now delineated molecular markers of the many B and T cell subsets that occupy distinct spatial and functional niches, much of this progress arose from the physical ability to sort, classify, and track Ag-specific cells.

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

DOI
10.4049/jimmunol.2100533

DDX17 is involved in DNA damage repair and modifies FUS toxicity in an RGG-domain dependent manner

NOMIS Researcher(s)

Published in

September 1, 2021

Mutations in the RNA binding protein, Fused in Sarcoma (FUS), lead to amyotrophic lateral sclerosis (ALS), the most frequent form of motor neuron disease. Cytoplasmic aggregation and defective DNA repair machinery are etiologically linked to mutant FUS-associated ALS. Although FUS is involved in numerous aspects of RNA processing, little is understood about the pathophysiological mechanisms of mutant FUS. Here, we employed RNA-sequencing technology in Drosophila brains expressing FUS to identify significantly altered genes and pathways involved in FUS-mediated neurodegeneration. We observed the expression levels of DEAD-Box Helicase 17 (DDX17) to be significantly downregulated in response to mutant FUS in Drosophila and human cell lines. Mutant FUS recruits nuclear DDX17 into cytoplasmic stress granules and physically interacts with DDX17 through the RGG1 domain of FUS. Ectopic expression of DDX17 reduces cytoplasmic mislocalization and sequestration of mutant FUS into cytoplasmic stress granules. We identified DDX17 as a novel regulator of the DNA damage response pathway whose upregulation repairs defective DNA damage repair machinery caused by mutant neuronal FUS ALS. In addition, we show DDX17 is a novel modifier of FUS-mediated neurodegeneration in vivo. Our findings indicate DDX17 is downregulated in response to mutant FUS, and restoration of DDX17 levels suppresses FUS-mediated neuropathogenesis and toxicity in vivo.

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

DOI
10.1007/s00401-021-02333-z

Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases

NOMIS Researcher(s)

Published in

September 1, 2021

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders, often considered as the extreme manifestations of a disease spectrum, as they share similar pathomechanisms. In support of this, pathological aggregation of the RNA/DNA binding proteins trans-activation response element DNA-binding protein 43 (TDP-43) or fused in sarcoma (FUS) is the pathological hallmark found in neurons and glial cells of subsets of patients affected by either condition (i.e., ALS/FTLD—TDP-43 or ALS/FTLD—FUS, respectively). Among glia, oligodendrocytes are the most abundant population, designated to ensheath the axons with myelin and to provide them with metabolic and trophic support. In this minireview, we recapitulate the neuropathological evidence for oligodendroglia impairment in ALS/FTLD. We then debate how TDP-43 and FUS target oligodendrocyte transcripts, thereby controlling their homeostatic abilities toward the axons. Finally, we discuss cellular and animal models aimed at investigating the functional consequences of manipulating TDP-43 and FUS in oligodendrocytes in vivo. Taken together, current data provide increasing evidence for an important role of TDP-43 and FUS-mediated oligodendroglia dysfunction in the pathogenesis of ALS/FTLD. Thus, targeting disrupted oligodendroglial functions may represent a new treatment approach for these conditions.

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

DOI
10.3389/fnins.2021.724891

Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoid receptor activity

NOMIS Researcher(s)

Published in

August 31, 2021

In macrophages, homeostatic and immune signals induce distinct sets of transcriptional responses, defining cellular identity and functional states. The activity of lineage-specific and signal-induced transcription factors are regulated by chromatin accessibility and other epigenetic modulators. Glucocorticoids are potent antiinflammatory drugs; however, the mechanisms by which they selectively attenuate inflammatory genes are not yet understood. Acting through the glucocorticoid receptor (GR), glucocorticoids directly repress inflammatory responses at transcriptional and epigenetic levels in macrophages. A major unanswered question relates to the sequence of events that result in the formation of repressive regions. In this study, we identify bromodomain containing 9 (BRD9), a component of SWI/SNF chromatin remodeling complex, as a modulator of glucocorticoid responses in macrophages. Inhibition, degradation, or genetic depletion of BRD9 in bone marrow-derived macrophages significantly attenuated their responses to both liposaccharides and interferon inflammatory stimuli. Notably, BRD9-regulated genes extensively overlap with those regulated by the synthetic glucocorticoid dexamethasone. Pharmacologic inhibition of BRD9 potentiated the antiinflammatory responses of dexamethasone, while the genetic deletion of BRD9 in macrophages reduced high-fat diet-induced adipose inflammation. Mechanistically, BRD9 colocalized at a subset of GR genomic binding sites, and depletion of BRD9 enhanced GR occupancy primarily at inflammatory-related genes to potentiate GR-induced repression. Collectively, these findings establish BRD9 as a genomic antagonist of GR at inflammatory-related genes in macrophages, and reveal a potential for BRD9 inhibitors to increase the therapeutic efficacies of glucocorticoids.

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

DOI
10.1073/pnas.2109517118

Does choice change preferences? An incentivized test of the mere choice effect

NOMIS Researcher(s)

Published in

August 15, 2021

Widespread evidence from psychology and neuroscience documents that previous choices unconditionally increase the later desirability of chosen objects, even if those choices were uninformative. This is problematic for economists who use choice data to estimate latent preferences, demand functions, and social welfare. The evidence on this mere choice effect, however, exhibits serious shortcomings which prevent evaluating its possible relevance for economics. In this paper, we present a novel, parsimonious experimental design to test for the economic validity of the mere choice effect addressing these shortcomings. Our design uses well-defined, monetary lotteries, all decisions are incentivized, and we effectively randomize participants’ initial choices without relying on deception. Results from a large, pre-registered online experiment find no support for the mere choice effect. Our results challenge conventional wisdom outside economics. The mere choice effect does not seem to be a concern for economics, at least in the domain of decision making under risk.

Research field(s)
Psychology & Cognitive Sciences

DOI
10.1007/s10683-021-09728-5

Tracking the transition to agriculture in Southern Europe through ancient DNA analysis of dental calculus

NOMIS Researcher(s)

Published in

August 10, 2021

Archaeological dental calculus, or mineralized plaque, is a key tool to track the evolution of oral microbiota across time in response to processes that impacted our culture and biology, such as the rise of farming during the Neolithic. However, the extent to which the human oral flora changed from prehistory until present has remained elusive due to the scarcity of data on the microbiomes of prehistoric humans. Here, we present our reconstruction of oral microbiomes via shotgun metagenomics of dental calculus in 44 ancient foragers and farmers from two regions playing a pivotal role in the spread of farming across Europe-the Balkans and the Italian Peninsula. We show that the introduction of farming in Southern Europe did not alter significantly the oral microbiomes of local forager groups, and it was in particular associated with a higher abundance of the species Olsenella sp. oral taxon 807. The human oral environment in prehistory was dominated by a microbial species, Anaerolineaceae bacterium oral taxon 439, that diversified geographically. A Near Eastern lineage of this bacterial commensal dispersed with Neolithic farmers and replaced the variant present in the local foragers. Our findings also illustrate that major taxonomic shifts in human oral microbiome composition occurred after the Neolithic and that the functional profile of modern humans evolved in recent times to develop peculiar mechanisms of antibiotic resistance that were previously absent.

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

DOI
10.1073/pnas.2102116118

Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB

NOMIS Researcher(s)

Published in

August 1, 2021

Methods to enhance adult neurogenesis by reprogramming glial cells into neurons enable production of new neurons in the adult nervous system. Development of therapeutically viable approaches to induce new neurons is now required to bring this concept to clinical application. Here, we successfully generate new neurons in the cortex and dentate gyrus of the aged adult mouse brain by transiently suppressing polypyrimidine tract binding protein 1 using an antisense oligonucleotide delivered by a single injection into cerebral spinal fluid. Radial glial-like cells and other GFAP-expressing cells convert into new neurons that, over a 2-month period, acquire mature neuronal character in a process mimicking normal neuronal maturation. The new neurons functionally integrate into endogenous circuits and modify mouse behavior. Thus, generation of new neurons in the dentate gyrus of the aging brain can be achieved with a therapeutically feasible approach, thereby opening prospects for production of neurons to replace those lost to neurodegenerative disease.

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

DOI
10.1038/s41593-021-00864-y

Social influence matters: We follow pandemic guidelines most when our close circle does

NOMIS Researcher(s)

Published in

August 1, 2021

Why do we adopt new rules, such as social distancing? Although human sciences research stresses the key role of social influence in behaviour change, most COVID-19 campaigns emphasize the disease’s medical threat. In a global data set (n = 6,675), we investigated how social influences predict people’s adherence to distancing rules during the pandemic. Bayesian regression analyses controlling for stringency of local measures showed that people distanced most when they thought their close social circle did. Such social influence mattered more than people thinking distancing was the right thing to do. People’s adherence also aligned with their fellow citizens, but only if they felt deeply bonded with their country. Self-vulnerability to the disease predicted distancing more for people with larger social circles. Collective efficacy and collectivism also significantly predicted distancing. To achieve behavioural change during crises, policymakers must emphasize shared values and harness the social influence of close friends and family.

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

DOI
10.1111/bjop.12491

Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial

NOMIS Researcher(s)

Published in

August 1, 2021

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P < 0.0001). Incidences of adverse events and deaths were similar between groups. This well-powered study suggests that N-terminal tau neutralization does not translate into clinical efficacy.

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

DOI
10.1038/s41591-021-01455-x

Body in the face of uncertainty: The role of autonomic arousal and interoception in decision-making under risk and ambiguity

NOMIS Researcher(s)

Published in

August 1, 2021

Influential theories posit that bodily responses are important for decision-making under uncertainty. However, the evidence of the role of our ability to perceive subtle bodily changes (interoception) in decision-making under uncertainty is mixed. These differences may arise from the fact that uncertainty, a part of daily decision-making, can be fractionated into risk (known probabilities) and ambiguity (unknown probabilities). Here we examine the role of arousal and interoception in shaping risky and ambiguous decisions. We measured skin conductance responses and heart rate changes while participants (N = 40) made gambling decisions in the context of risky and ambiguous lotteries. Results reveal that the anticipation phase produced the largest arousal responses, suggesting that the anticipation is a major contributor to arousal during gambling behavior, regardless of the uncertainty type. Moreover, physiological responses were higher following positive outcomes than negative outcomes. We did not find any direct relation between interoceptive dimensions and the attitudes toward risk and ambiguity. However, in those with higher interoceptive accuracy, skin conductance responses differentiated between risk and ambiguity as well as between the gamble phases (decision, anticipation, and outcome). Together, our findings demonstrate that decision-making under uncertainty is to some extent associated with individual differences in the ability both to generate and to perceive accurately subtle changes in bodily arousal during the decision-making process. However, these changes seem to be moderately related to the type of uncertainty (risk or ambiguity).

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

DOI
10.1111/psyp.13840

Dysregulation of brain and choroid plexus cell types in severe COVID-19

NOMIS Researcher(s)

Published in

July 22, 2021

Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms1–3. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease4–6. Synaptic signalling of upper-layer excitatory neurons—which are evolutionarily expanded in humans7 and linked to cognitive function8—is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.

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

DOI
10.1038/s41586-021-03710-0

The phase separation-dependent FUS interactome reveals nuclear and cytoplasmic function of liquid–liquid phase separation

NOMIS Researcher(s)

Published in

July 21, 2021

Liquid–liquid phase separation (LLPS) of proteins and RNAs has emerged as the driving force underlying the formation of membrane-less organelles. Such biomolecular condensates have various biological functions and have been linked to disease. The protein Fused in Sarcoma (FUS) undergoes LLPS and mutations in FUS have been causally linked to the motor neuron disease Amyotrophic Lateral Sclerosis (ALS-FUS). LLPS followed by aggregation of cytoplasmic FUS has been proposed to be a crucial disease mechanism. However, it is currently unclear how LLPS impacts the behaviour of FUS in cells, e.g. its interactome. Hence, we developed a method allowing for the purification of LLPS FUS-containing droplets from cell lysates. We observe substantial alterations in the interactome, depending on its biophysical state. While non-LLPS FUS interacts mainly with factors involved in pre-mRNA processing, LLPS FUS predominantly binds to proteins involved in chromatin remodelling and DNA damage repair. Interestingly, also mitochondrial factors are strongly enriched with LLPS FUS, providing a potential explanation for the observed changes in mitochondrial gene expression in mouse models of ALS-FUS. In summary, we present a methodology to investigate the interactomes of phase separating proteins and provide evidence that LLPS shapes the FUS interactome with implications for function and disease.

Research field(s)
Biochemistry & Molecular Biology

DOI
10.1093/nar/gkab582

Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors

NOMIS Researcher(s)

Published in

July 13, 2021

A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36−/− T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.

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

DOI
10.1016/j.immuni.2021.05.003

Habitual Actions, Propositional Knowledge, Motor Representations and Intentionality

NOMIS Researcher(s)

Published in

July 1, 2021

Habitual actions have a history of practice and repetition that frees us from attending to what we are doing. Nevertheless, habitual actions seem to be intentional. What does account for the intentionality of habitual actions if they are automatically performed and controlled? In this paper, we address a possible response to a particular version of this issue, that is, the problem of understanding how the intention to execute a habitual action, which comes in a propositional format, interlocks with motor representations, which come in a motoric-pragmatic format. In order to solve this issue, we propose an account according to which the propositional intentions and the motor representations related to our habitual actions interlock through executable action concepts. This allows us to maintain that habitual actions can be, at the same time, automatically initiated, performed, and controlled and, still, intentional.

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

DOI
10.1007/s11245-020-09723-0

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