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Publications in Health Sciences by NOMIS researchers

Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism

NOMIS Researcher(s)

Published in

June 1, 2019

Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Among these genes are progranulin (GRN) and the triggering receptor expressed on myeloid cells 2 (TREM2). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn−/− mice and compared their transcriptomes to those of Trem2−/− mice. Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn−/− mice showed a reciprocal activation of the MGnD molecular signature and suppression of gene characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro-2-deoxy-d-glucose)-μPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.

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

DOI
10.15252/emmm.201809711

Shared responsibility in collective decisions

NOMIS Researcher(s)

Published in

June 1, 2019

Research investigating collective decision-making has focused primarily on the improvement of accuracy in collective decisions and less on the motives that drive individuals to make these decisions. We argue that a strong but neglected motive for making collective decisions is minimizing the material and psychological burden of an individual’s responsibility. Making difficult decisions with others shields individuals from the consequences of negative outcomes by reducing regret, punishment and stress. Considering shared responsibility as a another key motivation to join groups helps understand behaviours with societal implications such as political voting, committing norm violations, predicting natural disasters and making health-related decisions.

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

DOI
10.1038/s41562-019-0596-4

Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1

NOMIS Researcher(s)

Published in

June 1, 2019

An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular–immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood–brain barrier as a possible target to treat age-related neurodegeneration.

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

DOI
10.1038/s41591-019-0440-4

Biodistribution and targeting properties of iron oxide nanoparticles for treatments of cancer and iron anemia disease

NOMIS Researcher(s)

Published in

May 28, 2019

IONP (iron oxide nanoparticles) commercialized for treatments of iron anemia or cancer diseases can be administered at doses exceeding 1 g per patient, indicating their bio-compatibility when they are prepared in the right conditions. Various parameters influence IONP biodistribution such as nanoparticle size, hydrophobicity/hydrophilicity, surface charge, core composition, coating properties, route of administration, quantity administered, and opsonization. IONP biodistribution trends include their capture by the reticuloendothelial system (RES), accumulation in liver and spleen, leading to nanoparticle degradation by macrophages and liver Kupffer cells, possibly followed by excretion in feces. To result in efficient tumor treatment, IONP need to reach the tumor in a sufficiently large quantity, using: (i) passive targeting, i.e. the extravasation of IONP through the blood vessel irrigating the tumor, (ii) molecular targeting achieved by a ligand bound to IONP specifically recognizing a cell receptor, and (iii) magnetic targeting in which a magnetic field gradient guides IONP towards the tumor. As a whole, targeting efficacy is relatively similar for different targeting, yielding a percentage of injected IONP in the tumor of 5.10−4% to 3%, 0.1% to 7%, and 5.10−3% to 2.6% for passive, molecular, and magnetic targeting, respectively. For the treatment of iron anemia disease, IONP are captured by the RES, and dissolved into free iron, which is then made available for the organism. For the treatment of cancer, IONP either deliver chemotherapeutic drugs to tumors, produce localized heat under the application of an alternating magnetic field or a laser, or activate in a controlled manner a sono-sensitizer following ultrasound treatment.

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

DOI
10.1080/17435390.2019.1572809

Clinical, pathophysiological and genetic features of motor symptoms in autosomal dominant Alzheimer’s disease

NOMIS Researcher(s)

Published in

May 1, 2019

Owing to an early and marked deposition of amyloid-β in the basal ganglia, autosomal dominant Alzheimer’s disease could distinctly involve motor symptoms. Therefore, we aimed to assess the prevalence and characteristics of motor signs in autosomal dominant Alzheimer’s disease. Baseline Unified Parkinson Disease Rating Scale part three scores (UPDRS-III) from 433 participants of the Dominantly Inherited Alzheimer’s Network observational study were analysed. Motor symptoms were scrutinized with respect to associations with mutation carrier status, mutation site within PSEN1, basal ganglia amyloid-β as measured by Pittsburgh compound B PET, estimated years to symptom onset and Clinical Dementia Rating Scale-Sum of Boxes. Motor findings in mutation carriers were compared to patients with sporadic Alzheimer’s disease using data of the National Alzheimer’s Coordination Center. Mutation carriers showed motor findings at a higher frequency (28.4% versus 12.8%; P < 0.001) and severity (mean UPDRS-III scores 2.0 versus 0.4; P < 0.001) compared to non-carriers. Eleven of the 27 UPDRS-III items were statistically more frequently affected in mutation carriers after adjustment for multiple comparisons. Ten of these 11 items were subscale components of bradykinesia. In cognitively asymptomatic mutation carriers, dysdiadochokinesia was more frequent compared to non-carriers (right hand: 3.8% versus 0%; adjusted P = 0.023; left: 4.4% versus 0.6%; adjusted P = 0.031). In this cohort, the positive predictive value for mutation carrier status in cognitively asymptomatic participants (50% a priori risk) of dysdiadochokinesia was 100% for the right and 87.5% for the left side. Mutation carriers with motor findings more frequently were basal ganglia amyloid-β positive (84% versus 63.3%; P = 0.006) and showed more basal ganglia amyloid-β deposition (Pittsburgh compound B-standardized uptake value ratio 2.472 versus 1.928; P = 0.002) than those without. Frequency and severity of motor findings were greater in post-codon 200 PSEN1 mutations (36%; mean UPDRS-III score 3.03) compared to mutations pre-codon 200 PSEN1 (19.3%, P = 0.022; 0.91, P = 0.013). In mutation carriers, motor symptom severity was significantly positively correlated with basal ganglia amyloid-β deposition, Clinical Dementia Rating scores and estimated years to symptom onset. Mutation carriers with a Clinical Dementia Rating global score of 2 exhibited more pronounced motor symptoms than sporadic Alzheimer's disease patients with the same Clinical Dementia Rating global score (mean UPDRS-III scores 20.71 versus 5.96; P < 0.001). With a prevalence of approximately 30% and increasing severity with progression of dementia, motor symptoms are proven as a clinically relevant finding in autosomal dominant Alzheimer's disease, in particular in advanced dementia stages, that correlates with deposition of amyloid-β in the basal ganglia. In a very small per cent of cognitively asymptomatic members of families with autosomal dominant Alzheimer's disease, dysdiadochokinesia may increase the chance of an individual's status as mutation carrier.

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

DOI
10.1093/brain/awz050

Multiple molecular pathways stimulating macroautophagy protect from alpha-synuclein-induced toxicity in human neurons

NOMIS Researcher(s)

Published in

May 1, 2019

Pathological aggregates of alpha-synuclein are the common hallmarks of synucleinopathies, including Parkinson’s disease. There is currently no disease-modifying therapy approved for neurodegenerative synucleinopathies. The induction of macroautophagy by small compounds may be a strategy to reduce the cellular alpha-synuclein burden and to confer neuroprotection. Therefore, in the present study, we investigated a broad spectrum of druggable molecular signaling pathways reported to induce macroautophagy in human cells and compared their protective efficacy against alpha-synuclein-induced toxicity in cultured human postmitotic dopaminergic neurons. Several compounds affecting different pathways were able to activate macroautophagy. All compounds that activated autophagy also protected against alpha-synuclein-induced toxicity. The compounds with the lowest effective concentrations were PI-103, L-690,330, and NF 449, making them particularly interesting for further investigations, including in vivo models. Our findings demonstrate that activation of macroautophagy, as a neuroprotective approach in synucleinopathies, is accessible to pharmacotherapy. Moreover, pharmacological activation of macroautophagy via diverse signaling pathways is effective to protect human dopaminergic neurons against alpha-synuclein-induced toxicity.

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

DOI
10.1016/j.neuropharm.2019.01.023

Seeing myself through my heart: Cortical processing of a single heartbeat speeds up self-face recognition

NOMIS Researcher(s)

Published in

May 1, 2019

Recent research has highlighted the contribution of interoceptive signals to different aspects of bodily self-consciousness (BSC) by means of the cardio-visual stimulation – i.e. perceiving a pulsing stimulus in synchrony with one’s own heart. Here, for the first time, we investigate the effects of individual heartbeats on a critical feature of BSC, namely the recognition of one’s own face. Across two studies, we explored the cardiac-timing effects on a classic self-face recognition task. In Study 1, participants saw morphed faces that contained different percentages of the self-face and that of another unfamiliar individual. Study 2 used a similar design, albeit participants saw morphed faces of the self-face and that of a familiar other to provide a better control of self-familiarity. Results from both studies consistently revealed that the cortical processing of cardiac afferent signals conveyed by the firing of arterial baroreceptors affects the speed, but not the accuracy, of self-face recognition, when a single picture is presented during cardiac systole, as compared to diastole. This effect is stronger and more stable for stimuli with more self-cues than other-cues and for ‘ambiguous’ stimuli – i.e. at the individual point of subjective equality. Results from Study 2 also revealed that cardiac effects on the speed of self-face recognition cannot be explained simply on the basis of the imbalanced familiarity between the self’s and other’s faces used. The present findings highlight the interoceptive contributions to self-recognition and may be expand our understanding of pathological disturbances of self-experience.

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

DOI
10.1016/j.biopsycho.2019.03.006

Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death

NOMIS Researcher(s)

Published in

April 17, 2019

TDP-43 aggregation is the major hallmark of multiple neurodegenerative diseases, including ALS and FTD. Gasset-Rosa et al. demonstrate that transient stress induces long-lasting cytoplasmic TDP-43 de-mixing independent of stress granules, driving nuclear import defects, nuclear TDP-43 clearance, and cell death.

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

DOI
10.1016/j.neuron.2019.02.038

Immunotherapy for neurodegeneration?

NOMIS Researcher(s)

Published in

April 12, 2019

Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion diseases such as Creutzfeldt-Jakob disease attack different parts of the central nervous system (CNS) and elicit distinct symptoms, yet they share many biochemical and neuropathological features. These include the formation of protein aggregates in the affected brain regions and progressive activation of non-neuronal cells in the brain that play crucial roles in immune responses. The activation of immune cells in the CNS (“neuroinflammation”) is prominent in these diseases. However, it remains unclear whether boosting or suppressing the immune system, in the brain or in the periphery, may attenuate neurodegeneration. In the case of extraneural prion infections, genetic or pharmacological ablation of components of the immune system, such as B cells and complement, can prevent disease (1). However, immunotherapies, which have been successful in treating certain types of cancer, have yet to reverse neurodegeneration in any patients. Therefore, the therapeutic promise of this approach remains debatable.

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

DOI
10.1126/science.aaw0685

CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

NOMIS Researcher(s)

Published in

April 11, 2019

Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR–Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.

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

DOI
10.1038/s41586-019-1088-4

SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease

NOMIS Researcher(s)

Published in

April 1, 2019

SARM1 (sterile α and HEAT/armadillo motif-containing protein) is a member of the MyD88 (myeloid differentiation primary response gene 88) family, which mediates innate immune responses. Because inactivation of SARM1 prevents various forms of axonal degeneration, we tested whether it might protect against prion-induced neurotoxicity. Instead, we found that SARM1 deficiency exacerbates the progression of prion pathogenesis. This deleterious effect was not due to SARM1-dependent modulation of prion-induced neuroinflammation, since microglial activation, astrogliosis, and brain cytokine profiles were not altered by SARM1 deficiency. Whole-transcriptome analyses indicated that SARM1 deficiency led to strong, selective overexpression of the pro-apoptotic gene XAF1 (X-linked inhibitor of apoptosis-associated factor 1). Consequently, the activity of pro-apoptotic caspases and neuronal death were enhanced in prion-infected SARM1−/− mice. These results point to an unexpected function of SARM1 as a regulator of prion-induced neurodegeneration and suggest that XAF1 might constitute a therapeutic target in prion disease.

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

DOI
10.1084/jem.20171885

Bisphenol a derivatives act as novel coactivator-binding inhibitors for estrogen receptor β

NOMIS Researcher(s)

Published in

April 1, 2019

Bisphenol A and its derivatives are recognized as endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is less well understood. Herein, we sought to identify novel ERβ ligands using a radioligand competitive binding assay to screen a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as both ERα agonists and ERβ antagonists. Docking simulations of these compounds and ERβ suggested that they bound not only to the canonical binding site of ERβ but also to the coactivator binding site located on the surface of the receptor, suggesting that they act as coactivator-binding inhibitors (CBIs). Receptor–ligand binding experiments using WT and mutated ERβ support the presence of a second ligand-interaction position at the coactivator-binding site in ERβ, and direct binding experiments of ERβ and a coactivator peptide confirmed that these compounds act as CBIs. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting critical insight for the future development of ER signaling–based drugs and their potential to function as endocrine disruptors.

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

DOI
10.1016/j.jbc.2021.101173

GeneMatch: A novel recruitment registry using at-home APOE genotyping to enhance referrals to Alzheimer’s prevention studies

NOMIS Researcher(s)

Published in

April 1, 2019

Introduction: Recruitment for Alzheimer’s disease (AD) prevention research studies is challenging because of lack of awareness among cognitively healthy adults coupled with the high screen fail rate due to participants not having a genetic risk factor or biomarker evidence of the disease. Participant recruitment registries offer one solution for efficiently and effectively identifying, characterizing, and connecting potential eligible volunteers to studies. Methods: Individuals aged 55-75 years who live in the United States and self-report not having a diagnosis of cognitive impairment such as MCI or dementia are eligible to join GeneMatch. Participants enroll online and are provided a cheek swab kit for DNA extraction and apolipoprotein E (APOE) genotyping. Participants are not told their APOE results, although the results may be used in part to help match participants to AD prevention studies. Results: As of August 2018, 75,351 participants had joined GeneMatch. Nearly 30% of participants have one APOE4 allele, and approximately 3% have two APOE4 alleles. The percentages of APOE4 heterozygotes and homozygotes are inversely associated with age (P <.001). Discussion: GeneMatch, the first trial-independent research enrollment program designed to recruit and refer cognitively healthy adults to AD prevention studies based in part on APOE test results, provides a novel mechanism to accelerate prescreening and enrollment for AD prevention trials.

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

DOI
10.1016/j.jalz.2018.12.007

The Solution Structure of FUS Bound to RNA Reveals a Bipartite Mode of RNA Recognition with Both Sequence and Shape Specificity

NOMIS Researcher(s)

Published in

February 7, 2019

FUS is an RNA binding protein associated with several neurodegenerative diseases, for which mode of nucleic acid binding has been elusive. Loughlin et al. solved the solution structure of FUS bound to RNA, revealing a sequence-specific recognition for a GGU motif and an unusual shape recognition of a stem loop by two separate domains.

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

DOI
10.1016/j.molcel.2018.11.012

Striatal amyloid is associated with tauopathy and memory decline in familial Alzheimer’s disease

NOMIS Researcher(s)

Published in

February 4, 2019

Background: Autosomal dominant Alzheimer’s disease (ADAD) is distinguished from late-onset AD by early striatal amyloid-β deposition. To determine whether striatal Pittsburgh compound B (PiB)-PET measurements of amyloid-β can help predict disease severity in ADAD, we compared relationships of striatal and neocortical PiB-PET to age, tau-PET, and memory performance in the Colombian Presenilin 1 E280A kindred. Methods: Fourteen carriers (age = 28-42, Mini-Mental State Examination = 26-30) and 20 age-matched non-carriers were evaluated using PiB, flortaucipir (FTP; tau), and memory testing (CERAD Word List Learning). PiB-PET signal was measured in neocortical and striatal aggregates. FTP-PET signal was measured in entorhinal cortex. Results: Compared to non-carriers, mutation carriers had age-related elevations in both neocortical and striatal PiB binding. The PiB elevation in carriers was significantly greater in the striatum than in the neocortex. In mutation carriers, PiB binding in both the neocortex and the striatum is related to entorhinal FTP; however, the association was stronger with the striatum. Only striatal PiB was associated with worse memory. Remarkably, PiB binding in the striatum, but not in the neocortex, predicted entorhinal FTP and lower memory scores after adjusting for age, indicating that striatal PiB identified the carriers with the most severe disease. Conclusions: Based on these preliminary cross-sectional findings, striatal PiB-PET measurements may offer particular value in the detection and tracking of preclinical ADAD, informing a mutation carrier’s prognosis and evaluating amyloid-β-modifying ADAD treatments.

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

DOI
10.1186/s13195-019-0468-1

Visualization of long-lived proteins reveals age mosaicism within nuclei of postmitotic cells

NOMIS Researcher(s)

Published in

February 1, 2019

Many adult tissues contain postmitotic cells as old as the host organism. Te only organelle that does not turn over in these cells is the nucleus, and its maintenance represents a formidable challenge, as it harbors regulatory proteins that persist throughout adulthood. Here we developed strategies to visualize two classes of such long-lived proteins, histones and nucleoporins, to understand the function of protein longevity in nuclear maintenance. Genome-wide mapping of histones revealed specifc enrichment of long-lived variants at silent gene loci. Interestingly, nuclear pores are maintained by piecemeal replacement of subunits, resulting in mosaic complexes composed of polypeptides with vastly different ages. In contrast, nondividing quiescent cells remove old nuclear pores in an ESCRT-dependent manner. Our fndings reveal distinct molecular strategies of nuclear maintenance, linking lifelong protein persistence to gene regulation and nuclear integrity.

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

DOI
10.1083/jcb.201809123

Review: Neuropathology of non-tau frontotemporal lobar degeneration

NOMIS Researcher(s)

Published in

February 1, 2019

Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome associated with frontotemporal lobar degeneration (FTLD) as a relatively consistent neuropathological hallmark feature. However, the discoveries in the past decade of many of the relevant pathological proteins aggregating in human FTD brains in addition to several new FTD causing gene mutations underlined that FTD is a diverse condition on the neuropathological and genetic basis. This resulted in a novel molecular classification of these conditions based on the predominant protein abnormality and allows most cases of FTD to be placed now into one of three broad molecular subgroups; FTLD with tau, TAR DNA-binding protein 43 or FET protein accumulation (FTLD-tau, FTLD-TDP and FTLD-FET respectively). This review will provide an overview of the molecular neuropathology of non-tau FTLD, insights into disease mechanisms gained from the study of human post mortem tissue as well as discussion of current controversies in the field.

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

DOI
10.1111/nan.12526

Two eARCHT3.0 lines for optogenetic silencing of dopaminergic and serotonergic neurons

NOMIS Researcher(s)

Published in

January 28, 2019

Dopaminergic and serotonergic neurons modulate and control processes ranging from reward signaling to regulation of motor outputs. Further, dysfunction of these neurons is involved in both degenerative and psychiatric disorders. Elucidating the roles of these neurons has been greatly facilitated by bacterial artificial chromosome (BAC) transgenic mouse lines expressing channelrhodopsin to readily enable cell-type specific activation. However, corresponding lines to silence these monoaminergic neurons have been lacking. We have generated two BAC transgenic mouse lines expressing the outward proton pump, enhanced ArchT3.0 (eArchT3.0), and GFP under control of the regulatory elements of either the dopamine transporter (DAT; Jax# 031663) or the tryptophan hydroxylase 2 (TPH2; Jax# 031662) gene locus. We demonstrate highly faithful and specific expression of these lines in dopaminergic and serotonergic neurons respectively. Additionally we validate effective and sensitive eArchT3.0-mediated silencing of these neurons using slice electrophysiology as well as with a well-established behavioral assay. These new transgenic tools will help expedite the study of dopaminergic and serotonergic system function in normal behavior and disease.

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

DOI
10.3389/fncir.2019.00004

Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing

NOMIS Researcher(s)

Published in

January 16, 2019

Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown whether these functions are carried out by subsets of microglia during different stages of development and adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, early postnatal, and adult mouse brains. We found that the majority of adult microglia expressing homeostatic genes are remarkably similar in transcriptomes, regardless of brain region. By contrast, early postnatal microglia are more heterogeneous. We discovered a proliferative-region-associated microglia (PAM) subset, mainly found in developing white matter, that shares a characteristic gene signature with degenerative disease-associated microglia (DAM). Such PAM have amoeboid morphology, are metabolically active, and phagocytose newly formed oligodendrocytes. This scRNA-seq atlas will be a valuable resource for dissecting innate immune functions in health and disease.

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

DOI
10.1016/j.neuron.2018.12.006

Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity

NOMIS Researcher(s)

Published in

January 7, 2019

One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1–4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4, 5]. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans [6, 7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.

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

DOI
10.1016/j.cub.2018.10.065

Coaching from the sidelines: the nuclear periphery in genome regulation

NOMIS Researcher(s)

Published in

January 1, 2019

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

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

DOI
10.1038/s41576-018-0063-5

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