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Publications in Health Sciences by NOMIS researchers

Automated production of human induced pluripotent stem cell-derived cortical and dopaminergic neurons with integrated live-cell monitoring

NOMIS Researcher(s)

Published in

August 1, 2020

Manual culture and differentiation protocols for human induced pluripotent stem cells (hiPSC) are difficult to standardize, show high variability and are prone to spontaneous differentiation into unwanted cell types. The methods are labor-intensive and are not easily amenable to large-scale experiments. To overcome these limitations, we developed an automated cell culture system coupled to a high-throughput imaging system and implemented protocols for maintaining multiple hiPSC lines in parallel and neuronal differentiation. We describe the automation of a short-term differentiation protocol using Neurogenin-2 (NGN2) over-expression to produce hiPSC-derived cortical neurons within 6‒8 days, and the implementation of a long-term differentiation protocol to generate hiPSC-derived midbrain dopaminergic (mDA) neurons within 65 days. Also, we applied the NGN2 approach to a small molecule-derived neural precursor cells (smNPC) transduced with GFP lentivirus and established a live-cell automated neurite outgrowth assay. We present an automated system with protocols suitable for routine hiPSC culture and differentiation into cortical and dopaminergic neurons. Our platform is suitable for long term hands-free culture and high-content/ high-throughput hiPSC-based compound, RNAi and CRISPR/Cas9 screenings to identify novel disease mechanisms and drug targets.

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

DOI
10.3791/61525

The cryo-em structure of the human uromodulin filament core reveals a unique assembly mechanism

NOMIS Researcher(s)

Published in

August 1, 2020

The glycoprotein uromodulin (UMOD) is the most abundant protein in human urine and forms filamentous homopolymers that encapsulate and aggregate uropathogens, promoting pathogen clearance by urine excretion. Despite its critical role in the innate immune response against urinary tract infections, the structural basis and mechanism of UMOD polymerization remained unknown. Here, we present the cryo-EM structure of the UMOD filament core at 3.5 Å resolution, comprised of the bipartite zona pellucida (ZP) module in a helical arrangement with a rise of ~65 Å and a twist of ~180°. The immunoglobulin-like ZPN and ZPC subdomains of each monomer are separated by a long linker that interacts with the preceding ZPC and following ZPN subdomains by β-sheet complementation. The unique filament architecture suggests an assembly mechanism in which subunit incorporation could be synchronized with proteolytic cleavage of the C-terminal pro-peptide that anchors assembly-incompetent UMOD precursors to the membrane.

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

DOI
10.7554/ELIFE.60265

The somatotopy of observed emotions

NOMIS Researcher(s)

Published in

August 1, 2020

The ability to experience others’ emotional states is a key component in social interactions. Uniquely among sensorimotor regions, the somatosensory cortex (SCx) plays an especially important role in human emotion understanding. While distinct emotions are experienced in specific parts of the body, it remains unknown whether the SCx exhibits somatotopic activations to different emotional expressions. In the current study, we investigated if the affective response triggered by observing others’ emotional face expressions leads to differential activations in SCx. Participants performed a visual facial emotion discrimination task while we measured changes in SCx topographic EEG activity by tactually stimulating two body-parts representative of the upper and lower limbs, the finger and the toe respectively. The results of the study showed an emotion specific response in the finger SCx when observing angry as opposed to sad emotional expressions, after controlling for carry-over effects of visual evoked activity. This dissociation to observed emotions was not present in toe somatosensory responses. Our results suggest that somatotopic activations of the SCx to discrete emotions might play a crucial role in understanding others’ emotions.

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

DOI
10.1016/j.cortex.2020.04.002

Ageing hallmarks exhibit organ-specific temporal signatures

NOMIS Researcher(s)

Published in

July 23, 2020

Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified—such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1—these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2—or ‘Mouse Ageing Cell Atlas’—which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions—including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue—including plasma cells that express immunoglobulin J—which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.

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

DOI
10.1038/s41586-020-2499-y

Persistent Differences in Brain Structure in Developmental Dyscalculia: A Longitudinal Morphometry Study

NOMIS Researcher(s)

Published in

July 17, 2020

Developmental dyscalculia (DD) is a learning disability affecting the acquisition of numerical-arithmetical skills. Affected people show persistent deficits in number processing, which are associated with aberrant brain activation and structure. Reduced gray matter has been reported in DD for the parietal cortex including the intraparietal sulcus (IPS), but also the frontal and occipito-temporal cortex. Furthermore, dyscalculics show white matter differences for instance in the inferior (ILF) and superior longitudinal fasciculus (SLF). However, the longitudinal development of these structural differences is unknown. Therefore, our goal was to investigate the developmental trajectory of gray and white matter in children with and without DD. In this longitudinal study, neuropsychological measures and T1-weighted structural images were collected twice with an interval of 4 years from 13 children with DD (8.2–10.4 years) and 10 typically developing (TD) children (8.0–10.4 years). Voxel-wise estimation of gray and white matter volumes was assessed using voxel-based morphometry for longitudinal data. The present findings reveal for the first time that DD children show persistently reduced gray and white matter volumes over development. Reduced gray matter was found in the bilateral inferior parietal lobes including the IPS, supramarginal gyri, left precuneus, cuneus, right superior occipital gyrus, bilateral inferior and middle temporal gyri, and insula. White matter volumes were reduced in the bilateral ILF and SLF, inferior fronto-occipital fasciculus (IFOF), corticospinal tracts, and right anterior thalamic radiation (ATR). Behaviorally, children with DD performed significantly worse in various numerical tasks at baseline and follow-up, corroborating persistent deficits in number processing. The present results are in line with the literature showing that children with DD have reduced gray and white matter volumes in the numerical network. Our study further sheds light on the trajectory of brain development, revealing that these known structural differences in the long association fibers and the adjacent regions of the temporal- and frontoparietal cortex persist in dyscalculic children from childhood into adolescence. In conclusion, our results underscore that DD is a persistent learning disorder accompanied by deficits in number processing and reduced gray and white matter volumes in number related brain areas.

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

DOI
10.3389/fnhum.2020.00272

Human Stem Cell Resources Are an Inroad to Neandertal DNA Functions

NOMIS Researcher(s)

Published in

July 14, 2020

Induced pluripotent stem cells (iPSCs) from diverse humans offer the potential to study human functional variation in controlled culture environments. A portion of this variation originates from an ancient admixture between modern humans and Neandertals, which introduced alleles that left a phenotypic legacy on individual humans today. Here, we show that a large iPSC repository harbors extensive Neandertal DNA, including alleles that contribute to human phenotypes and diseases, encode hundreds of amino acid changes, and alter gene expression in specific tissues. We provide a database of the inferred introgressed Neandertal alleles for each individual iPSC line, together with the annotation of the predicted functional variants. We also show that transcriptomic data from organoids generated from iPSCs can be used to track Neandertal-derived RNA over developmental processes. Human iPSC resources provide an opportunity to experimentally explore Neandertal DNA function and its contribution to present-day phenotypes, and potentially study Neandertal traits. In this article, Camp and colleagues show that large stem cell resources carry extensive Neandertal DNA, including many functionally relevant Neandertal alleles. The authors demonstrate that organoid systems can be used to explore Neandertal DNA activity during development.

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

DOI
10.1016/j.stemcr.2020.05.018

A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function

NOMIS Researcher(s)

Published in

July 14, 2020

Regulation of Foxp3 expression is central to Treg cell development and function. Loo et al. performed a genome-wide CRISPR screen and identified the Brd9-containing ncBAF complex as a key regulator of Foxp3 and a subset of its target genes, which could be targeted to cripple Treg cell function and improve anti-tumor immunity.

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

DOI
10.1016/j.immuni.2020.06.011

Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning

NOMIS Researcher(s)

Published in

July 13, 2020

Background: P301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in the brainstem, hippocampus, and neocortex, leading to neuronal loss and cognitive deterioration. However, there is hitherto only sparse documentation of the role of neuroinflammation in tau mouse models. Thus, we analyzed longitudinal microglial activation by small animal 18 kDa translocator protein positron-emission-tomography (TSPO μPET) imaging in vivo, in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism. Methods: Transgenic P301S (n = 33) and wild-type (n = 18) female mice were imaged by 18F-GE-180 TSPO μPET at the ages of 1.9, 3.9, and 6.4 months. We conducted behavioral testing in the Morris water maze, 18F-fluordesoxyglucose (18F-FDG) μPET, and AT8 tau immunohistochemistry at 6.3-6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO μPET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-β mouse models. Results: TSPO expression in all target regions of P301S mice increased exponentially from 1.9 to 6.4 months, leading to significant differences in the contrasts with wild-type mice at 6.4 months (+ 11-23%, all p < 0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-β mouse models. Spatial learning and glucose metabolism of AT8-positive P301S mice were significantly impaired at 6.3-6.5 months compared to the wild-type group. Longitudinal increases in TSPO expression predicted greater tau accumulation and lesser spatial learning performance at 6.3-6.7 months. Conclusions: Monitoring of TSPO expression as a surrogate of microglial activation in P301S tau transgenic mice by μPET indicates a delayed time course when compared to amyloid-β mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-β mouse models. The contribution of microglial response to pathology accompanying amyloid-β and tau over-expression merits further investigation.

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

DOI
10.1186/s12974-020-01883-5

Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons

NOMIS Researcher(s)

Published in

July 2, 2020

Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.

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

DOI
10.1016/j.molcel.2020.05.016

A metabolic handbook for the COVID-19 pandemic

NOMIS Researcher(s)

Published in

July 1, 2020

For infectious-disease outbreaks, clinical solutions typically focus on efficient pathogen destruction. However, the COVID-19 pandemic provides a reminder that infectious diseases are complex, multisystem conditions, and a holistic understanding will be necessary to maximize survival. For COVID-19 and all other infectious diseases, metabolic processes are intimately connected to the mechanisms of disease pathogenesis and the resulting pathology and pathophysiology, as well as the host defence response to the infection. Here, I examine the relationship between metabolism and COVID-19. I discuss why preexisting metabolic abnormalities, such as type 2 diabetes and hypertension, may be important risk factors for severe and critical cases of infection, highlighting parallels between the pathophysiology of these metabolic abnormalities and the disease course of COVID-19. I also discuss how metabolism at the cellular, tissue and organ levels might be harnessed to promote defence against the infection, with a focus on disease-tolerance mechanisms, and speculate on the long-term metabolic consequences for survivors of COVID-19.

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

DOI
10.1038/s42255-020-0237-2

Dynamic regulation of histone modifications and long-range chromosomal interactions during postmitotic transcriptional reactivation

NOMIS Researcher(s)

Published in

July 1, 2020

During mitosis, transcription of genomic DNA is dramatically reduced, before it is reactivated during nuclear reformation in anaphase/telophase. Many aspects of the underlying principles that mediate transcriptional memory and reactivation in the daughter cells remain unclear. Here, we used ChIP-seq on synchronized cells at different stages after mitosis to generate genome-wide maps of histone modifications. Combined with EU-RNA-seq and Hi-C analyses, we found that during prometaphase, promoters, enhancers, and insulators retain H3K4me3 and H3K4me1, while losing H3K27ac. Enhancers globally retaining mitotic H3K4me1 or locally retaining mitotic H3K27ac are associated with cell type-specific genes and their transcription factors for rapid transcriptional activation. As cells exit mitosis, promoters regain H3K27ac, which correlates with transcriptional reactivation. Insulators also gain H3K27ac and CCCTC-binding factor (CTCF) in anaphase/telophase. This increase of H3K27ac in anaphase/telophase is required for posttranscriptional activation and may play a role in the establishment of topologically associating domains (TADs). Together, our results suggest that the genome is reorganized in a sequential order, in which histone methylations occur first in prometaphase, histone acetylation, and CTCF in anaphase/telophase, transcription in cytokinesis, and long-range chromatin interactions in early G1. We thus provide insights into the histone modification landscape that allows faithful reestablishment of the transcriptional program and TADs during cell division.

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

DOI
10.1101/GAD.335794.119

Baseline demographic, clinical, and cognitive characteristics of the Alzheimer’s Prevention Initiative (API) Autosomal-Dominant Alzheimer’s Disease Colombia Trial

NOMIS Researcher(s)

Published in

July 1, 2020

Introduction: The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo-controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60-year-old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non-carriers who receive placebo. Methods: Of the 252 enrolled, we present data on a total of 242 mutation carriers and non-carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. Results: We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non-carriers, 30 to 53 years of age. Carriers were significantly younger than non-carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. Discussion: Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non-carriers. Their demographic characteristics are representative of the local population.

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

DOI
10.1002/alz.12109

Systematic review and analysis of human proteomics aging studies unveils a novel proteomic aging clock and identifies key processes that change with age

NOMIS Researcher(s)

Published in

July 1, 2020

The development of clinical interventions that significantly improve human healthspan requires robust markers of biological age as well as thoughtful therapeutic targets. To promote these goals, we performed a systematic review and analysis of human aging and proteomics studies. The systematic review includes 36 different proteomics analyses, each of which identified proteins that significantly changed with age. We discovered 1,128 proteins that had been reported by at least two or more analyses and 32 proteins that had been reported by five or more analyses. Each of these 32 proteins has known connections relevant to aging and age-related disease. GDF15, for example, extends both lifespan and healthspan when overexpressed in mice and is additionally required for the anti-diabetic drug metformin to exert beneficial effects on body weight and energy balance. Bioinformatic enrichment analyses of our 1,128 commonly identified proteins heavily implicated processes relevant to inflammation, the extracellular matrix, and gene regulation. We additionally propose a novel proteomic aging clock comprised of proteins that were reported to change with age in plasma in three or more different studies. Using a large patient cohort comprised of 3,301 subjects (aged 18–76 years), we demonstrate that this clock is able to accurately predict human age.

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

DOI
10.1016/j.arr.2020.101070

Prion infection, transmission, and cytopathology modeled in a low-biohazard human cell line

NOMIS Researcher(s)

Published in

June 30, 2020

Transmission of prion infectivity to susceptible murine cell lines has simplified prion titration assays and has greatly reduced the need for animal experimentation. However, murine cell models suffer from technical and biological constraints. Human cell lines might be more useful, but they are much more biohazardous and are often poorly infectible. Here, we describe the human clonal cell line hovS, which lacks the human PRNP gene and expresses instead the ovine PRNP VRQ allele. HovS cells were highly susceptible to the PG127 strain of sheep-derived murine prions, reaching up to 90% infected cells in any given culture and were maintained in a continuous infected state for at least 14 passages. Infected hovS cells produced proteinase K–resistant prion protein (PrPSc), pelletable PrP aggregates, and bona fide infectious prions capable of infecting further generations of naïve hovS cells and mice expressing the VRQ allelic variant of ovine PrPC. Infection in hovS led to prominent cytopathic vacuolation akin to the spongiform changes observed in individuals suffering from prion diseases. In addition to expanding the toolbox for prion research to human experimental genetics, the hovS cell line provides a human-derived system that does not require human prions. Hence, the manipulation of scrapie-infected hovS cells may present fewer biosafety hazards than that of genuine human prions.

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

DOI
10.26508/LSA.202000814

In vivo activation of a conserved microRNA program induces mammalian heart regeneration

NOMIS Researcher(s)

Published in

June 26, 2020

Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.

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

DOI
10.1016/j.stem.2014.10.003

Cryo-Electron Tomography Reveals the Complex Ultrastructural Organization of Multicellular Filamentous Chloroflexota (Chloroflexi) Bacteria

NOMIS Researcher(s)

Published in

June 26, 2020

The cell biology of Chloroflexota is poorly studied. We applied cryo-focused ion beam milling and cryo-electron tomography to study the ultrastructural organization of thermophilic Roseiflexus castenholzii and Chloroflexus aggregans, and mesophilic “Ca. Viridilinea mediisalina.” These species represent the three main lineages within a group of multicellular filamentous anoxygenic phototrophic Chloroflexota bacteria belonging to the Chloroflexales order. We found surprising structural complexity in the Chloroflexales. As with filamentous cyanobacteria, cells of C. aggregans and “Ca. Viridilinea mediisalina” share the outer membrane-like layers of their intricate multilayer cell envelope. Additionally, cells of R. castenholzii and “Ca. Viridilinea mediisalina” are connected by septal channels that resemble cyanobacterial septal junctions. All three strains possess long pili anchored close to cell-to-cell junctions, a morphological feature comparable to that observed in cyanobacteria. The cytoplasm of the Chloroflexales bacteria is crowded with intracellular organelles such as different types of storage granules, membrane vesicles, chlorosomes, gas vesicles, chemoreceptor-like arrays, and cytoplasmic filaments. We observed a higher level of complexity in the mesophilic strain compared to the thermophilic strains with regards to the composition of intracellular bodies and the organization of the cell envelope. The ultrastructural details that we describe in these Chloroflexales bacteria will motivate further cell biological studies, given that the function and evolution of the many discovered morphological traits remain enigmatic in this diverse and widespread bacterial group.

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

DOI
10.3389/fmicb.2020.01373

Reversing a model of Parkinson’s disease with in situ converted nigral neurons

NOMIS Researcher(s)

Published in

June 25, 2020

Parkinson’s disease is characterized by loss of dopamine neurons in the substantia nigra1. Similar to other major neurodegenerative disorders, there are no disease-modifying treatments for Parkinson’s disease. While most treatment strategies aim to prevent neuronal loss or protect vulnerable neuronal circuits, a potential alternative is to replace lost neurons to reconstruct disrupted circuits2. Here we report an efficient one-step conversion of isolated mouse and human astrocytes to functional neurons by depleting the RNA-binding protein PTB (also known as PTBP1). Applying this approach to the mouse brain, we demonstrate progressive conversion of astrocytes to new neurons that innervate into and repopulate endogenous neural circuits. Astrocytes from different brain regions are converted to different neuronal subtypes. Using a chemically induced model of Parkinson’s disease in mouse, we show conversion of midbrain astrocytes to dopaminergic neurons, which provide axons to reconstruct the nigrostriatal circuit. Notably, re-innervation of striatum is accompanied by restoration of dopamine levels and rescue of motor deficits. A similar reversal of disease phenotype is also accomplished by converting astrocytes to neurons using antisense oligonucleotides to transiently suppress PTB. These findings identify a potentially powerful and clinically feasible approach to treating neurodegeneration by replacing lost neurons.

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

DOI
10.1038/s41586-020-2388-4

Nuclear Periphery Takes Center Stage: The Role of Nuclear Pore Complexes in Cell Identity and Aging

NOMIS Researcher(s)

Published in

June 17, 2020

In recent years, the nuclear pore complex (NPC) has emerged as a key player in genome regulation and cellular homeostasis. New discoveries have revealed that the NPC has multiple cellular functions besides mediating the molecular exchange between the nucleus and the cytoplasm. In this review, we discuss non-transport aspects of the NPC focusing on the NPC-genome interaction, the extreme longevity of the NPC proteins, and NPC dysfunction in age-related diseases. The examples summarized herein demonstrate that the NPC, which first evolved to enable the biochemical communication between the nucleus and the cytoplasm, now doubles as the gatekeeper of cellular identity and aging. Cho and Hetzer discuss recent studies that have established the nuclear pore complex as a key regulator of transcription control of cell identity genes and have linked its functional decline to premature, physiological, and pathological aging.

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

DOI
10.1016/j.neuron.2020.05.031

Genome-wide transcriptomics identifies an early preclinical signature of prion infection

NOMIS Researcher(s)

Published in

June 1, 2020

The clinical course of prion diseases is accurately predictable despite long latency periods, suggesting that prion pathogenesis is driven by precisely timed molecular events. We constructed a searchable genome-wide atlas of mRNA abundance and splicing alterations during the course of disease in prion-inoculated mice. Prion infection induced PrP-dependent transient changes in mRNA abundance and processing already at eight weeks post inoculation, well ahead of any neuropathological and clinical signs. In contrast, microglia-enriched genes displayed an increase simultaneous with the appearance of clinical signs, whereas neuronal-enriched transcripts remained unchanged until the very terminal stage of disease. This suggests that glial pathophysiology, rather than neuronal demise, could be the final driver of disease. The administration of young plasma attenuated the occurrence of early mRNA abundance alterations and delayed signs in the terminal phase of the disease. The early onset of prion-induced molecular changes might thus point to novel biomarkers and potential interventional targets.

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

DOI
10.1371/journal.ppat.1008653

Copathology in Progressive Supranuclear Palsy: Does It Matter?

NOMIS Researcher(s)

Published in

June 1, 2020

Background: The influence of concomitant brain pathologies on the progression rate in PSP is unclear. Objectives: To analyze the frequency and severity of copathologies and their impact on the progression in PSP. Methods: We analyzed clinic-pathological features of 101 PSP patients. Diagnoses and stages of copathologies were established according to standardized criteria, including Alzheimer’s disease–related pathology, argyrophilic grains, Lewy-related pathology, transactive response DNA-binding protein 43 pathology, fused in sarcoma pathology, cerebral amyloid angiopathy, and small vessel disease. Demographic data and major clinical milestones (frequency and latency to onset) were extracted from patients’ files. Results: Only 8% of 101 patients presented with pure PSP pathology without any copathology. Alzheimer’s disease–related pathology was the most frequent (84%), followed by argyrophilic grains (58%), both occurring as single copathology or in combination with other proteinopathies or cerebrovascular disease. Lewy-related and transactive response DNA-binding protein 43 copathology occurred rarely (8% and 6%, respectively). Fused in sarcoma–positive cases were not found. While being common, copathology was mostly mild in severity, with the exception of frequently widespread argyrophilic grains. Small vessel disease was also frequent (65%). Cerebral amyloid angiopathy occurred only in the presence of Alzheimer’s disease–related changes (25%). The copathologies did not have major impact on prevalence and time frame of major disease milestones. Conclusions: In PSP, concomitant neurodegenerative proteinopathies or cerebrovascular diseases are frequent, but generally mild in severity. Our data confirmed that four repeat tau is still the most relevant target for PSP, whereas the impact of copathologies on progression rate appears to be of less importance. This is relevant information for the development of disease-modifying therapies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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

DOI
10.1002/mds.28011

Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional and longitudinal cohort study

NOMIS Researcher(s)

Published in

June 1, 2020

Background: Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer’s disease kindred. Methods: In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer’s disease Colombian kindred aged 8–75 years with no other neurological or health conditions were recruited from the Alzheimer’s Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers. Findings: We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset. Interpretation: Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Banner Alzheimer's Foundation, COLCIENCIAS, the Torsten Söderberg Foundation, the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and the Swedish state under the ALF-agreement.

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

DOI
10.1016/S1474-4422(20)30137-X

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