Insight
is our reward
Search

Publications in Health Sciences by NOMIS researchers

Longer metaphase and fewer chromosome segregation errors in modern human than Neanderthal brain development

NOMIS Researcher(s)

Published in

July 29, 2022

Since the ancestors of modern humans separated from those of Neanderthals, around 100 amino acid substitutions spread to essentially all modern humans. The biological significance of these changes is largely unknown. Here, we examine all six such amino acid substitutions in three proteins known to have key roles in kinetochore function and chromosome segregation and to be highly expressed in the stem cells of the developing neocortex. When we introduce these modern human-specific substitutions in mice, three substitutions in two of these proteins, KIF18a and KNL1, cause metaphase prolongation and fewer chromosome segregation errors in apical progenitors of the developing neocortex. Conversely, the ancestral substitutions cause shorter metaphase length and more chromosome segregation errors in human brain organoids, similar to what we find in chimpanzee organoids. These results imply that the fidelity of chromosome segregation during neocortex development improved in modern humans after their divergence from Neanderthals.

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

DOI
10.1126/sciadv.abn7702

On the content of Peripersonal visual experience

NOMIS Researcher(s)

Published in

July 1, 2022

In a recent paper, ‘Peripersonal perception in action’ (Synthese, 2018), Frédérique de Vignemont tackles the problem of defining what is peculiar to the visual perception of objects falling within the peripersonal space of the observer, i.e. the space immediately surrounding the body, and which is commonly described as the space in which action takes place. In this paper, I first discuss the proposal offered by de Vignemont about what characterizes peripersonal perception. Then, I suggest an extension of this account that offers a meticulous description of the nature of the Content of Peripersonal Visual Experience – a topic never explicitly considered in the philosophical literature on vision – by discussing some peculiar features of it that, as recognized also by de Vignemont’s account, still need to be explained. In particular, I offer a philosophical examination of the specificity of peripersonal visual experience, in relation to its phenomenological dimension, its optical mechanisms and its neurophysiological underpinnings, in the light of our best theories from vision science, and in comparison to the visual experience of other visual spaces.

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

DOI
10.1007/s11097-021-09733-2

The clinically relevant CYP2C8*3 and CYP2C9*2 haplotype is inherited from Neandertals

NOMIS Researcher(s)

Published in

July 1, 2022

Genetic variation in genes encoding cytochrome P450 enzymes influences the metabolism of drugs and endogenous compounds. The locus containing the cytochrome genes CYP2C8 and CYP2C9 on chromosome 10 exhibits linkage disequilibrium between the CYP2C8*3 and CYP2C9*2 alleles, forming a haplotype of ~300 kilobases. This haplotype is associated with altered metabolism of several drugs, most notably reduced metabolism of warfarin and phenytoin, leading to toxicity at otherwise therapeutic doses. Here we show that this haplotype is inherited from Neandertals.

Research field(s)
Health Sciences, Clinical Medicine, Pharmacology & Pharmacy

DOI
10.1038/s41397-022-00284-6

The evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals

NOMIS Researcher(s)

Published in

July 1, 2022

Proteins associated with the spindle apparatus, a cytoskeletal structure that ensures the proper segregation of chromosomes during cell division, experienced an unusual number of amino acid substitutions in modern humans after the split from the ancestors of Neandertals and Denisovans. Here, we analyze the history of these substitutions and show that some of the genes in which they occur may have been targets of positive selection. We also find that the two changes in the kinetochore scaffold 1 (KNL1) protein, previously believed to be specific to modern humans, were present in some Neandertals. We show that the KNL1 gene of these Neandertals shared a common ancestor with present-day Africans about 200,000 years ago due to gene flow from the ancestors (or relatives) of modern humans into Neandertals. Subsequently, some non-Africans inherited this modern human-like gene variant from Neandertals, but none inherited the ancestral gene variants. These results add to the growing evidence of early contacts between modern humans and archaic groups in Eurasia and illustrate the intricate relationships among these groups.

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

DOI
10.7554/elife.75464

Absolute quantification of plasma mitochondrial DNA by droplet digital PCR marks COVID-19 severity over time during intensive care unit admissions

NOMIS Researcher(s)

Published in

July 1, 2022

Increased plasma mitochondrial DNA concentrations are associated with poor outcomes in multiple critical illnesses, including COVID19. However, current methods of cell-free mitochondrial DNA quantification in plasma are time-consuming and lack reproducibility. Here, we used next-generation sequencing to characterize the size and genome location of circulating mitochondrial DNA in critically ill subjects with COVID-19 to develop a facile and optimal method of quantification by droplet digital PCR. Sequencing revealed a large percentage of small mitochondrial DNA fragments in plasma with wide variability in coverage by genome location. We identified probes for the mitochondrial DNA genes, cytochrome B and NADH dehydrogenase 1, in regions of relatively high coverage that target small sequences potentially missed by other methods. Serial assessments of absolute mitochondrial DNA concentrations were then determined in plasma from 20 critically ill subjects with COVID-19 without a DNA isolation step. Mitochondrial DNA concentrations on the day of enrollment were increased significantly in patients with moderate or severe acute respiratory distress syndrome (ARDS) compared with those with no or mild ARDS. Comparisons of mitochondrial DNA concentrations over time between patients with no/mild ARDS who survived, patients with moderate/severe ARDS who survived, and nonsurvivors showed the highest concentrations in patients with more severe disease. Absolute mitochondrial DNA quantification by droplet digital PCR is time-efficient and reproducible; thus, we provide a valuable tool and rationale for future studies evaluating mitochondrial DNA as a real-time biomarker to guide clinical decision-making in critically ill subjects with COVID-19.

Research field(s)
Health Sciences, Clinical Medicine, Respiratory System

DOI
10.1152/ajplung.00128.2022

Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle stem-cell niche

NOMIS Researcher(s)

Published in

July 1, 2022

Maintenance of tissue homeostasis is dependent on the communication between stem cells and supporting cells in the same niche. Regulatory T cells (Treg cells) are emerging as a critical component of the stem-cell niche for supporting their differentiation. How Treg cells sense dynamic signals in this microenvironment and communicate with stem cells is mostly unknown. In the present study, by using hair follicles (HFs) to study Treg cell–stem cell crosstalk, we show an unrecognized function of the steroid hormone glucocorticoid in instructing skin-resident Treg cells to facilitate HF stem-cell (HFSC) activation and HF regeneration. Ablation of the glucocorticoid receptor (GR) in Treg cells blocks hair regeneration without affecting immune homeostasis. Mechanistically, GR and Foxp3 cooperate in Treg cells to induce transforming growth factor β3 (TGF-β3), which activates Smad2/3 in HFSCs and facilitates HFSC proliferation. The present study identifies crosstalk between Treg cells and HFSCs mediated by the GR–TGF-β3 axis, highlighting a possible means of manipulating Treg cells to support tissue regeneration.

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

DOI
10.1038/s41590-022-01244-9

Estrogen-Related Receptor γ Maintains Pancreatic Acinar Cell Function and Identity by Regulating Cellular Metabolism

NOMIS Researcher(s)

Published in

July 1, 2022

Background & Aims: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production. Methods: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in 2 distinct human pancreatitis cohorts. Results: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss of ERRγ in primary acini abrogates messenger RNA expression and protein levels of mitochondrial oxidative phosphorylation complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared with normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants for ERRγ that are associated with chronic pancreatitis. Conclusions: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

Research field(s)
Health Sciences, Clinical Medicine, Gastroenterology & Hepatology

DOI
10.1053/j.gastro.2022.04.013

40S hnRNP particles are a novel class of nuclear biomolecular condensates

NOMIS Researcher(s)

Published in

June 24, 2022

Heterogenous nuclear ribonucleoproteins (hnRNPs) are abundant proteins implicated in various steps of RNA processing that assemble on nuclear RNA into larger complexes termed 40S hnRNP particles. Despite their initial discovery 55 years ago, our understanding of these intriguing macromolecular assemblies remains limited. Here, we report the biochemical purification of native 40S hnRNP particles and the determination of their complete protein composition by label-free quantitative mass spectrometry, identifying A-group and C-group hnRNPs as the major protein constituents. Isolated 40S hnRNP particles dissociate upon RNA digestion and can be reconstituted in vitro on defined RNAs in the presence of the individual protein components, demonstrating a scaffolding role for RNA in nucleating particle formation. Finally, we revealed their nanometer scale, condensate-like nature, promoted by intrinsically disordered regions of A-group hnRNPs. Collectively, we identify nuclear 40S hnRNP particles as novel dynamic biomolecular condensates.

Research field(s)
Biochemistry & Molecular Biology

DOI
10.1093/nar/gkac457

Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons

NOMIS Researcher(s)

Published in

June 7, 2022

Aggregation of the multifunctional RNA-binding protein TDP-43 defines large subgroups of amyotrophic lateral sclerosis and frontotemporal dementia and correlates with neurodegeneration in both diseases. In disease, characteristic C-terminal fragments of ~25 kDa (“TDP-25”) accumulate in cytoplasmic inclusions. Here, we analyze gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics, and functional assays. In neurons, cytoplasmic TDP-25 inclusions are amorphous, and photobleaching experiments reveal gel-like biophysical properties that are less dynamic than nuclear TDP-43. Compared with full-length TDP-43, the TDP-25 interactome is depleted of low-complexity domain proteins. TDP-25 inclusions are enriched in 26S proteasomes adopting exclusively substrate-processing conformations, suggesting that inclusions sequester proteasomes, which are largely stalled and no longer undergo the cyclic conformational changes required for proteolytic activity. Reporter assays confirm that TDP-25 impairs proteostasis, and this inhibitory function is enhanced by ALS-causing TDP-43 mutations. These findings support a patho-physiological relevance of proteasome dysfunction in ALS/FTD.

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

DOI
10.15252/embr.202153890

Drug screen in iPSC-Neurons identifies nucleoside analogs as inhibitors of (G4C2)n expression in C9orf72 ALS/FTD

NOMIS Researcher(s)

Published in

June 7, 2022

An intronic (G4C2)n expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia primarily through gain-of-function mechanisms: the accumulation of sense and antisense repeat RNA foci and dipeptide repeat (DPR) proteins (poly-GA/GP/GR/PA/PR) translated from repeat RNA. To therapeutically block this pathway, we screen a library of 1,430 approved drugs and known bioactive compounds in patient-derived induced pluripotent stem cell-derived neurons (iPSC-Neurons) for inhibitors of DPR expression. The clinically used guanosine/cytidine analogs decitabine, entecavir, and nelarabine reduce poly-GA/GP expression, with decitabine being the most potent. Hit compounds nearly abolish sense and antisense RNA foci and reduce expression of the repeat-containing nascent C9orf72 RNA transcript and its mature mRNA with minimal effects on global gene expression, suggesting that they specifically act on repeat transcription. Importantly, decitabine treatment reduces (G4C2)n foci and DPRs in C9orf72 BAC transgenic mice. Our findings suggest that nucleoside analogs are a promising compound class for therapeutic development in C9orf72 repeat-expansion-associated disorders.

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

DOI
10.1016/j.celrep.2022.110913

Benthic Biofilms in Glacier-Fed Streams from Scandinavia to the Himalayas Host Distinct Bacterial Communities Compared with the Streamwater

NOMIS Researcher(s)

Published in

June 1, 2022

Microbial life in glacier-fed streams (GFSs) is dominated by benthic biofilms which fulfill critical ecosystem processes. However, it remains unclear how the bacterial communities of these biofilms assemble in stream ecosystems characterized by rapid turnover of benthic habitats and high suspended sediment loads. Using16S rRNA gene amplicon sequence data collected from 54 GFSs across the Himalayas, European Alps, and Scandinavian Mountains, we found that benthic biofilms harbor bacterial communities that are distinct from the bacterial assemblages suspended in the streamwater. Our data showed a decrease in species richness in the benthic biofilms compared to the bacterial cells putatively free-living in the water. The benthic biofilms also differed from the suspended water fractions in terms of community composition. Differential abundance analyses highlighted bacterial families that were specific to the benthic biofilms and the suspended assemblages. Notably, source-sink models suggested that the benthic biofilm communities are not simply a subset of the suspended assemblages. Rather, we found evidence that deterministic processes (e.g., species sorting) shape the benthic biofilm communities. This is unexpected given the high vertical mixing of water and contained bacterial cells in GFSs and further highlights the benthic biofilm mode of life as one that is determined through niche-related processes. Our findings therefore reveal a “native” benthic biofilm community in an ecosystem that is currently threatened by climate-induced glacier shrinkage.

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

DOI
10.1128/aem.00421-22

Metabolic Messengers: fibroblast growth factor 1

NOMIS Researcher(s)

Published in

June 1, 2022

null

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

DOI
10.1038/s42255-022-00580-2

Multicenter Randomized Trial of Methylprednisolone vs. Intravenous Immunoglobulins to Treat the Pediatric Inflammatory Multisystem Syndrome—Temporally Associated With SARS-CoV-2 (PIMS-TS): Protocol of the Swissped RECOVERY Trial

NOMIS Researcher(s)

Published in

May 20, 2022

Introduction: In 2020, a new disease entitled Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C), emerged, with thousands of children affected globally. There is no available evidence based on randomized controlled trials (RCT) to date on the two most commonly used immunomodulatory treatments, intravenous immunoglobulins (IVIG) and corticosteroids. Therefore, the Swissped RECOVERY trial was conducted to assess whether intravenous (IV) methylprednisolone shortens hospital length of stay compared with IVIG. Methods and Analysis: Swissped RECOVERY is an ongoing investigator-initiated, open-label, multicenter two-arm RCT in children and adolescents <18 years hospitalized with a diagnosis of PIMS-TS. The trial is recruiting at 10 sites across Switzerland. Patients diagnosed with PIMS-TS are randomized 1:1 to methylprednisolone IV (10 mg/kg/day for 3 days) or IVIG (2 g/kg as a single dose). The primary outcome is hospital length of stay censored at day 28, death, or discharge (whichever is first). The target total sample size is ~80 patients 1:1 randomized to each study arm. Ancillary and exploratory studies on inflammation, vaccination acceptance and coverage, long-term outcomes, and healthcare costs are pre-planned. Significance: Currently, robust trial evidence for the treatment of PIMS-TS is lacking, with a controversy surrounding the use of corticosteroids vs. IVIG. This trial will provide evidence for the effectiveness and safety of these two treatments. Ethics and Dissemination: The study protocol, which was designed based on the U.K. RECOVERY trial, the patient information and consent forms, and other study-specific study documents were approved by the local ethics committees (Project ID: 2021-00362). Registration Details: The study is registered on the Swiss National Clinical Trials Portal (SNCTP000004720) and Clinicaltrials.gov (NCT 04826588).

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

DOI
10.3389/fped.2022.905046

Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17

NOMIS Researcher(s)

Published in

May 19, 2022

Recent understanding of how the systemic environment shapes the brain throughout life has led to numerous intervention strategies to slow brain ageing1–3. Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds4,5. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures. Using SLAMseq to metabolically label nascent mRNA, we identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.

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

DOI
10.1038/s41586-022-04722-0

The Diversity Gap: When Diversity Matters for Knowledge

NOMIS Researcher(s)

Published in

May 1, 2022

Can diversity make for better science? Although diversity has ethical and political value, arguments for its epistemic value require a bridge between normative and mechanistic considerations, demonstrating why and how diversity benefits collective intelligence. However, a major hurdle is that the benefits themselves are rather mixed: Quantitative evidence from psychology and behavioral sciences sometimes shows a positive epistemic effect of diversity, but often shows a null effect, or even a negative effect. Here we argue that to make progress with these why and how questions, we need first to rethink when one ought to expect a benefit of cognitive diversity. In doing so, we highlight that the benefits of cognitive diversity are not equally distributed about collective intelligence tasks and are best seen for complex, multistage, creative problem solving, during problem posing and hypothesis generation. Throughout, we additionally outline a series of mechanisms relating diversity and problem complexity, and show how this perspective can inform metascience questions.

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

DOI
10.1177/17456916211006070

Limited proteolysis–mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures

NOMIS Researcher(s)

Published in

May 1, 2022

Cerebrospinal fluid (CSF) proteins and their structures have been implicated in aging and neurodegenerative diseases. In the present study, we used limited proteolysis–mass spectrometry (LiP–MS) to screen for new aging-associated changes in the CSF proteome using a modified analysis. We found 38 protein groups that change in abundance with aging, predominantly immunoglobulins of the IgM subclass. We discovered six high-confidence candidates that underwent structural changes with aging, of which Kng1, Itih2, Lp-PLA2 and 14-3-3 proteins have binding partners or chemical forms known previously to change in the brains of patients with Alzheimer’s disease. Orthogonal validation by western blotting identified that the LiP–MS hit Cd5l forms a covalent complex with IgM in mouse and human CSF, the abundance of which increases with aging. In human CSF, SOMAmer probe signals for all six LiP–MS hits were associated with cognitive function and/or biomarkers of neurodegeneration, especially 14-3-3 proteins YWHAB and YWHAZ. Together, our findings show that LiP–MS can uncover age-related structural changes in CSF with relevance to neurodegeneration.

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

DOI
10.1038/s43587-022-00196-x

Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation

NOMIS Researcher(s)

Published in

April 19, 2022

Post-translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA-binding protein TAR DNA-binding protein (TDP-43), is hyperphosphorylated in disease on several C-terminal serine residues, a process generally believed to promote TDP-43 aggregation. Here, we however find that Casein kinase 1δ-mediated TDP-43 hyperphosphorylation or C-terminal phosphomimetic mutations reduce TDP-43 phase separation and aggregation, and instead render TDP-43 condensates more liquid-like and dynamic. Multi-scale molecular dynamics simulations reveal reduced homotypic interactions of TDP-43 low-complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP-43, but suppress accumulation of TDP-43 in membrane-less organelles and promote its solubility in neurons. We speculate that TDP-43 hyperphosphorylation may be a protective cellular response to counteract TDP-43 aggregation.

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

DOI
10.15252/embj.2021108443

Rhesus monkeys have an interoceptive sense of their beating hearts

NOMIS Researcher(s)

Published in

April 19, 2022

The sensation of internal bodily signals, such as when your stomach is contracting or your heart is beating, plays a critical role in broad biological and psychological functions ranging from homeostasis to emotional experience and self-awareness. The evolutionary origins of this capacity and, thus, the extent to which it is present in nonhuman animals remain unclear. Here, we show that rhesus monkeys (Macaca mulatta) spend significantly more time viewing stimuli presented asynchronously, as compared to synchronously, with their heartbeats. This is consistent with evidence previously shown in human infants using a nearly identical experimental paradigm, suggesting that rhesus monkeys have a human-like capacity to integrate interoceptive signals from the heart with exteroceptive audiovisual information. As no prior work has demonstrated behavioral evidence of innate cardiac interoceptive ability in nonhuman animals, these results have important implications for our understanding of the evolution of this ability and for establishing rhesus monkeys as an animal model for human interoceptive function and dysfunction.We anticipate that this work may also provide an important model for future psychiatric research, as disordered interoceptive processing is implicated in a wide variety of psychiatric conditions.

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

DOI
10.1073/pnas.2119868119

Obesity alters pathology and treatment response in inflammatory disease

NOMIS Researcher(s)

Published in

April 14, 2022

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1–7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.

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

DOI
10.1038/s41586-022-04536-0

Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS

NOMIS Researcher(s)

Published in

April 1, 2022

Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated SOD1 mutations (D90Ahom, R115Ghet or A4Vhet) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90Ahom MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115Ghet and A4Vhet mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS.

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

DOI
10.3390/cells11071246

Load More