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Publications in Health Sciences by NOMIS researchers

The binding orientations of structurally-related ligands can differ; A cautionary note

NOMIS Researcher(s)

Published in

June 1, 2017

Crystal structures can identify ligand-receptor interactions and assist the development of novel therapeutics, but experimental challenges sometimes necessitate the use of homologous proteins. Tropisetron is an orthosteric ligand at both 5-HT3 and α7 nACh receptors and its binding orientation has been determined in the structural homologue AChBP (pdbid: 2WNC). Co-crystallisation with a structurally-related ligand, granisetron, reveals an almost identical orientation (pdbid; 2YME). However, there is a >1000-fold difference in the affinity of tropisetron at 5-HT3 versus α7 nACh receptors, and α7 nACh receptors do not bind granisetron. These striking pharmacological differences prompt questions about which receptor the crystal structures most closely represent and whether the ligand orientations are correct. Here we probe the binding orientation of tropisetron and granisetron at 5-HT3 receptors by in silico modelling and docking, radioligand binding on cysteine-substituted 5-HT3 receptor mutants transiently expressed in HEK 293 cells, and synthetic modification of the ligands. For 15 of the 23 cysteine substitutions, the effects on tropisetron and granisetron were different. Structure-activity relationships on synthesised derivatives of both ligands were also consistent with different orientations, revealing that contrary to the crystallographic evidence from AChBP, the two ligands adopt different orientations in the 5-HT3 receptor binding site. Our results show that even quite structurally similar molecules can adopt different orientations in the same binding site, and that caution may be needed when using homologous proteins to predict ligand binding.

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

DOI
10.1016/j.neuropharm.2017.01.023

From the body’s viscera to the body’s image: Is there a link between interoception and body image concerns?

NOMIS Researcher(s)

Published in

June 1, 2017

Interoception, the sense of the physiological condition of the body originating from within its internal organs, and body image, namely the perception, feelings and attitudes one has about one’s body, are two fundamental components of our sense of personal identity and overall well-being. However, the relation between interoception and body image remains poorly understood. We here review recent behavioural and neuroimaging evidence from non-clinical and clinical populations (e.g. eating disorders) to propose that basic interoceptive processes and interoceptive awareness may crucially contribute to the complex formation of body image, as well as to its disturbances. In particular, lower interoceptive accuracy and awareness are associated with body-image concerns. We provide a potential mechanistic explanation of the link between interoception and body image, which aims to integrate interoceptive and exteroceptive representations of the body. The suggested link between interoception and body image can inform new empirically testable hypotheses on the underlying neurocognitive processes that are central to body image concerns and disturbances, and motivate relevant clinical implications.

Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Behavioral Science & Comparative Psychology

DOI
10.1016/j.neubiorev.2017.03.017

Global Representations of Goal-Directed Behavior in Distinct Cell Types of Mouse Neocortex

NOMIS Researcher(s)

Published in

May 17, 2017

The successful planning and execution of adaptive behaviors in mammals may require long-range coordination of neural networks throughout cerebral cortex. The neuronal implementation of signals that could orchestrate cortex-wide activity remains unclear. Here, we develop and apply methods for cortex-wide Ca2+ imaging in mice performing decision-making behavior and identify a global cortical representation of task engagement encoded in the activity dynamics of both single cells and superficial neuropil distributed across the majority of dorsal cortex. The activity of multiple molecularly defined cell types was found to reflect this representation with type-specific dynamics. Focal optogenetic inhibition tiled across cortex revealed a crucial role for frontal cortex in triggering this cortex-wide phenomenon; local inhibition of this region blocked both the cortex-wide response to task-initiating cues and the voluntary behavior. These findings reveal cell-type-specific processes in cortex for globally representing goal-directed behavior and identify a major cortical node that gates the global broadcast of task-related information.

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

DOI
10.1016/j.neuron.2017.04.017

Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins

NOMIS Researcher(s)

Published in

May 1, 2017

Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly-GA, poly-GP, and poly-PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly-GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly-GA and cerebellar extracts of C9orf72 patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80. Treatment with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity of C9orf72 brain extracts. Poly-GA-directed immunotherapy may thus reduce DPR aggregation and disease progression in C9orf72 ALS/FTD.

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

DOI
10.15252/emmm.201607054

Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia

NOMIS Researcher(s)

Published in

May 1, 2017

Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the MAPT H1 haplotype), we observed that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in cis-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA p < 2.0 × 10−16). Functionally, we found that these shared risk genes were associated with protein interaction and gene co-expression networks and showed enrichment for several neurodevelopmental pathways. Our findings suggest: (1) novel genetic overlap between CBD and PSP beyond the MAPT locus; (2) strong ties between CBD and FTD through the MAPT clade, and (3) unique combinations of overlapping genes that may, in part, influence selective regional or neuronal vulnerability observed in specific tauopathies.

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

DOI
10.1007/s00401-017-1693-y

Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene

NOMIS Researcher(s)

Published in

April 21, 2017

Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those without known mutation. Four patients with Motor Neurone Disease (MND) with C9orf72 expansions and 10 healthy controls were also studied. Semi-quantitative analysis assessed hnRNP staining intensity in dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx) in the different pathological and genetic groups.Immunostaining for hnRNP A1, A2/B1 and A3 revealed no consistent changes in pattern or amount of physiological staining across any of the pathological or genetic groups. No immunostaining of any inclusions resembling TDP-43 immunoreactive neuronal cytoplasmic inclusions or dystrophic neurites, was seen in either Tcx or DG of the hippocampus in any of the FTLD cases investigated for hnRNP A1, A2/B1 and A3. However, immunostaining for hnRNP A3 showed that inclusion bodies, resembling those TDP-43 negative, p62-immunopositive structures containing dipeptide repeat proteins (DPR) were variably observed in hippocampus and cerebellum. The proportion of cases showing hnRNP A3-immunoreactive DPR, and the number of hnRNP A3-positive inclusions within cases, was significantly greater in DG than in cells of CA4 region and cerebellum, but the latter was significantly less in all three regions compared to that detected by p62 immunostaining.

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

DOI
10.1186/s40478-017-0437-5

The binding orientation of epibatidine at α7 nACh receptors

NOMIS Researcher(s)

Published in

April 1, 2017

Epibatidine is an alkaloid toxin that binds with high affinity to nicotinic and muscarinic acetylcholine receptors, and has been extensively used as a research tool. To examine binding interactions at the nicotinic receptor, it has been co-crystallised with the structural homologue acetylcholine binding protein (AChBP; PDB ID 2BYQ), and with an AChBP chimaera (3SQ6) that shares 64% sequence identity with the α7 nACh receptor. However, the binding orientations revealed by AChBP co-crystal structures may not precisely represent their receptor homologues and experimental evidence is needed to verify the ligand poses. Here we identify potential binding site interactions between epibatidine and AChBP residues, and substitute equivalent positions in the α7 nACh receptor. The effects of these are probed by [3H]epibatidine binding following the expression α7 nACh receptor cysteine mutants in HEK 293 cells. Of the sixteen mutants created, the affinity of epibatidine was unaffected by the substitutions Q55C, L106C, L116C, T146C, D160C and S162C, reduced by C186A and C187A, increased by Q114C and S144C, and abolished by W53C, Y91C, N104C, W145C, Y184C and Y191C. These results are consistent with the predicted orientations in AChBP and suggest that epibatidine is likely to occupy a similar location at α7 nACh receptors. We speculate that steric constraints placed upon the C-5 position of the pyridine ring in 3SQ6 may account for the relatively poor affinities of epibatidine derivatives that are substituted at this position.

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

DOI
10.1016/j.neuropharm.2017.01.008

PERK activation mitigates tau pathology in vitro and in vivo

NOMIS Researcher(s)

Published in

March 1, 2017

The RNA-like endoplasmic reticulum kinase (PERK) is genetically associated with the tauopathy progressive supranuclear palsy (PSP). To elucidate the functional mechanisms underlying this association, we explored PERK activity in brains of PSP patients and its function in three tauopathy models (cultured human neurons overexpressing 4-repeat wild-type tau or treated with the environmental neurotoxin annonacin, and P301S tau transgenic mice). In vitro, treatment with a pharmacological PERK activator CCT020312 or PERK overexpression reduced tau phosphorylation, tau conformational change and 4-repeat tau isoforms, and increased cell viability. In vivo, the PERK activator significantly improved memory and locomotor function, reduced tau pathology, and prevented dendritic spine and motoneuron loss in P301S tau mice. Importantly, the PERK substrate EIF2A, mediating some detrimental effects of PERK signaling, was downregulated in PSP brains and tauopathy models, suggesting that the alternative PERK–NRF2 pathway accounts for these beneficial effects in the context of tauopathies. In summary, PERK activation may be a novel strategy to treat PSP and eventually other tauopathies.

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

DOI
10.15252/emmm.201606664

Cardiac afferent activity modulates the expression of racial stereotypes

NOMIS Researcher(s)

Published in

January 17, 2017

Negative racial stereotypes tend to associate Black people with threat. This often leads to the misidentification of harmless objects as weapons held by a Black individual. Yet, little is known about how bodily states impact the expression of racial stereotyping. By tapping into the phasic activation of arterial baroreceptors, known to be associated with changes in the neural processing of fearful stimuli, we show activation of race-Threat stereotypes synchronized with the cardiovascular cycle. Across two established tasks, stimuli depicting Black or White individuals were presented to coincide with either the cardiac systole or diastole. Results show increased race-driven misidentification of weapons during systole, when baroreceptor afferent firing is maximal, relative to diastole. Importantly, a third study examining the positive Black-Athletic stereotypical association fails to demonstrate similar modulations by cardiac cycle. We identify a body-brain interaction wherein interoceptive cues can modulate threat appraisal and racially biased behaviour in context-dependent ways.

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

DOI
10.1038/ncomms13854

Intraneuronal protein aggregation as a trigger for inflammation and neurodegeneration in the aging brain

NOMIS Researcher(s)

Published in

January 1, 2017

Age is, by far, the greatest risk factor for Alzheimer’s disease (AD) , yet few A Ddrug candidateshave been generated that target pathways specifically associated with the aging process itself. Two ubiquitous features of the aging brain are the intracellular accumulation of aggregated proteins and inflammation. As intraneuronal amyloid protein is detected before markers of inflammation, we argue that old, age-associated, aggregated proteins in neurons can induce inflammation, resulting inmultiple forms of brain toxicities. The consequence is the increased risk of old, age-associated, neurodegenerative diseases. As most of these diseases are associated with the accumulation of aggregated proteins, it is possible that any therapeutic that reduces intracellular protein aggregation will benefit all. – Currais, A., Fischer, W., Maher, P., Schubert, D. Intraneuronal protein aggregation as a trigger for inflammation and neurodegeneration in the aging brain.

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

DOI
10.1096/fj.201601184

Mentalizing homeostasis: The social origins of interoceptive inference

NOMIS Researcher(s)

Published in

January 1, 2017

Is the self already relational in its very bodily foundations? The question of whether our mental life is initially and primarily shaped by embodied dimensions of the individual or by interpersonal relations is debated in many fields, including psychology, philosophy, psychoanalysis, and more recently, cognitive neuroscience. In this interdisciplinary target article, we put forward the radical claim that even some of the most minimal aspects of selfhood, namely the feeling qualities associated with being an embodied subject, are fundamentally shaped by embodied interactions with other people in early infancy and beyond. Such embodied interactions allow the developing organism to mentalize its homeostatic regulation. In other words, embodied interactions contribute directly to the building of mental models of the infant’s physiological states, given the need to maintain such states within a given dynamic range despite internal or external perturbations. Specifically, our position rests on the following three propositions: (1) the progressive integration and organization of sensory and motor signals constitutes the foundations of the minimal self, a process which we have linked to contemporary, computational models of brain function and named “embodied mentalization”; (2) interactions with other people are motivated and constrained by the same principles that govern the “mentalization” of sensorimotor signals in the individual-and hence the mentalization of one’s body can include signals from other bodies in physical proximity and interaction, especially in interaction with particular bodies. (3) Crucially, given the dependency of humans in early infancy, there is a “homeostatically necessary” plethora of such embodied “proximal” interactions, especially as regards interoception. Collectively, such experiences of proximal intercorporeality “sculpt” the mentalization process and hence the constitution of the minimal self, including the progressive sophistication of mental distinctions between “subject-object,” “self-other” and even “pleasure-pain.” Finally, we explore notions of cardiac and more broadly interoceptive awareness as later, cognitive acquisitions that allow us to progressively solidify such distinctions, as well as understand and empathise with other people.

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

DOI
10.1080/15294145.2017.1294031

In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration

NOMIS Researcher(s)

Published in

December 1, 2016

Targeted genome editing via engineered nucleases is an exciting area of biomedical research and holds potential for clinical applications. Despite rapid advances in the field, in vivo targeted transgene integration is still infeasible because current tools are inefficient, especially for non-dividing cells, which compose most adult tissues. This poses a barrier for uncovering fundamental biological principles and developing treatments for a broad range of genetic disorders. Based on clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) technology, here we devise a homology-independent targeted integration (HITI) strategy, which allows for robust DNA knock-in in both dividing and non-dividing cells in vitro and, more importantly, in vivo (for example, in neurons of postnatal mammals). As a proof of concept of its therapeutic potential, we demonstrate the efficacy of HITI in improving visual function using a rat model of the retinal degeneration condition retinitis pigmentosa. The HITI method presented here establishes new avenues for basic research and targeted gene therapies.

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

DOI
10.1038/nature20565

Surgical correction of septal deviation after Le Fort I osteotomy

NOMIS Researcher(s)

Published in

December 1, 2016

Background: The Le Fort I osteotomy is one of the most widely used and useful procedure to correct the dentofacial deformities of the midface. The changes of the maxilla position affect to overlying soft tissue including the nasal structure. Postoperative nasal septum deviation is a rare and unpredicted outcome after the surgery. There are only a few reports reporting the management of this complication. Case Presentation: In our department, three cases of the postoperative nasal septum deviation after the Le Fort I osteotomy had been experienced. Via limited intraoral circumvestibular incision, anterior maxilla, the nasal floor, and the anterior aspect of the septum were exposed. The cartilaginous part of the nasal septum was resected and repositioned to the midline and the anterior nasal spine was recontoured. Alar cinch suture performed again to prevent the sides of nostrils from flaring outwards. After the procedure, nasal septum deviation was corrected and the esthetic outcomes were favorable. Conclusion: Careful extubation, intraoperative management of nasal septum, and meticulous examination of pre-existing nasal septum deviation is important to avoid postoperative nasal septum deviation. If it existed after the maxillary osteotomy, septum repositioning technique of the current report can successfully correct the postoperative septal deviation.

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

DOI
10.1186/s40902-016-0067-z

Disease Tolerance Trick or Treat: Give Your Brain Something Good to Eat

NOMIS Researcher(s)

Published in

September 8, 2016

The reprioritization of feeding motivations during disease is proposed to optimize host defense strategies against infection. Now, Wang et al. identify that sickness-induced anorexia differentially shapes the metabolic requirements of cellular stress adaptations, leading to opposite impact on disease tolerance upon bacterial versus viral infections.

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

DOI
10.1016/j.cell.2016.08.034

Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition

NOMIS Researcher(s)

Published in

September 1, 2016

Intronic hexanucleotide (G4C2) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins (DPR). Repeat-dependent toxicity may affect nuclear import. hnRNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G4C2 repeat RNA. We now report that a reduction of nuclear hnRNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hnRNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hnRNPA3. Reduced nuclear hnRNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci.

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

DOI
10.15252/embr.201541724

Minor intron splicing is regulated by FUS and affected by ALS-associated FUS mutants

NOMIS Researcher(s)

Published in

July 15, 2016

Fused in sarcoma (FUS) is a ubiquitously expressed RNA-binding protein proposed to function in various RNA metabolic pathways, including transcription regulation, pre-mRNA splicing, RNA transport and microRNA processing. Mutations in the FUS gene were identified in patients with amyotrophic lateral sclerosis (ALS), but the pathomechanisms by which these mutations cause ALS are not known. Here, we show that FUS interacts with the minor spliceosome constituent U11 snRNP, binds preferentially to minor introns and directly regulates their removal. Furthermore, a FUS knockout in neuroblastoma cells strongly disturbs the splicing of minor intron-containing mRNAs, among them mRNAs required for action potential transmission and for functional spinal motor units. Moreover, an ALS-associated FUS mutant that forms cytoplasmic aggregates inhibits splicing of minor introns by trapping U11 and U12 snRNAs in these aggregates. Collectively, our findings suggest a possible pathomechanism for ALS in which mutated FUS inhibits correct splicing of minor introns in mRNAs encoding proteins required for motor neuron survival.

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

DOI
10.15252/embj.201593791

Cooperative microbial tolerance behaviors in host-microbiota mutualism

NOMIS Researcher(s)

Published in

June 2, 2016

Animal defense strategies against microbes are most often thought of as a function of the immune system, the primary function of which is to sense and kill microbes through the execution of resistance mechanisms. However, this antagonistic view creates complications for our understanding of beneficial host-microbe interactions. Pathogenic microbes are described as employing a few common behaviors that promote their fitness at the expense of host health and fitness. Here, a complementary framework is proposed to suggest that, in addition to pathogens, beneficial microbes have evolved behaviors to manipulate host processes in order to promote their own fitness and do so through the promotion of host health and fitness. In this Perspective, I explore the idea that patterns or behaviors traditionally ascribed to pathogenic microbes are also employed by beneficial microbes to promote host tolerance defense strategies. Such strategies would promote host health without having a negative impact on microbial fitness and would thereby yield cooperative evolutionary dynamics that are likely required to drive mutualistic co-evolution of hosts and microbes.

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

DOI
10.1016/j.cell.2016.05.049

Understanding the molecular mechanisms of reprogramming

NOMIS Researcher(s)

Published in

May 6, 2016

Despite the profound and rapid advancements in reprogramming technologies since the generation of the first induced pluripotent stem cells (iPSCs) in 2006[1], the molecular basics of the process and its implications are still not fully understood. Recent work has suggested that a subset of TFs, so called “Pioneer TFs”, play an important role during the stochastic phase of iPSC reprogramming [2-6]. Pioneer TFs activities differ from conventional transcription factors in their mechanism of action. They bind directly to condensed chromatin and elicit a series of chromatin remodeling events that lead to opening of the chromatin. Chromatin decondensation by pioneer factors progressively occurs during cell division and in turn exposes specific gene promoters in the DNA to which TFs can now directly bind to promoters that are readily accessible[2, 6]. Here, we will summarize recent advancements on our understanding of the molecular mechanisms underlying reprogramming to iPSC as well as the implications that pioneer Transcription Factor activities might play during different lineage conversion processes.

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

DOI
10.1016/j.bbrc.2015.11.120

TAM receptors regulate multiple features of microglial physiology

NOMIS Researcher(s)

Published in

April 14, 2016

Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we show that the TAM receptor tyrosine kinases Mer and Axl regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson’s disease. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.

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

DOI
10.1038/nature17630

Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS-FUS

NOMIS Researcher(s)

Published in

April 1, 2016

Deposition of the nuclear DNA/RNA-binding protein Fused in sarcoma (FUS) in cytosolic inclusions is a common hallmark of some cases of frontotemporal lobar degeneration (FTLD-FUS) and amyotrophic lateral sclerosis (ALS-FUS). Whether both diseases also share common pathological mechanisms is currently unclear. Based on our previous finding that FUS deposits are hypomethylated in FTLD-FUS but not in ALS-FUS, we have now investigated whether genetic or pharmacological inactivation of Protein arginine methyltransferase 1 (PRMT1) activity results in unmethylated FUS or in alternatively methylated forms of FUS. To do so, we generated FUS-specific monoclonal antibodies that specifically recognize unmethylated arginine (UMA), monomethylated arginine (MMA) or asymmetrically dimethylated arginine (ADMA). Loss of PRMT1 indeed not only results in an increase of UMA FUS and a decrease of ADMA FUS, but also in a significant increase of MMA FUS. Compared to ADMA FUS, UMA and MMA FUS exhibit much higher binding affinities to Transportin-1, the nuclear import receptor of FUS, as measured by pull-down assays and isothermal titration calorimetry. Moreover, we show that MMA FUS occurs exclusively in FTLD-FUS, but not in ALS-FUS. Our findings therefore provide additional evidence that FTLD-FUS and ALS-FUS are caused by distinct disease mechanisms although both share FUS deposits as a common denominator.

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

DOI
10.1007/s00401-016-1544-2

Establishment of human iPSC-based models for the study and targeting of glioma initiating cells

NOMIS Researcher(s)

Published in

February 22, 2016

Glioma tumour-initiating cells (GTICs) can originate upon the transformation of neural progenitor cells (NPCs). Studies on GTICs have focused on primary tumours from which GTICs could be isolated and the use of human embryonic material. Recently, the somatic genomic landscape of human gliomas has been reported. RTK (receptor tyrosine kinase) and p53 signalling were found dysregulated in â1/490% and 86% of all primary tumours analysed, respectively. Here we report on the use of human-induced pluripotent stem cells (hiPSCs) for modelling gliomagenesis. Dysregulation of RTK and p53 signalling in hiPSC-derived NPCs (iNPCs) recapitulates GTIC properties in vitro. In vivo transplantation of transformed iNPCs leads to highly aggressive tumours containing undifferentiated stem cells and their differentiated derivatives. Metabolic modulation compromises GTIC viability. Last, screening of 101 anti-cancer compounds identifies three molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results highlight the potential of hiPSCs for studying human tumourigenesis.

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

DOI
10.1038/ncomms10743

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