Recent publications from our research center
TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells
Alpizar YA, Boonen B, Sanchez A, Jung C, López-Requena A, Naert R, Steelant B, Luyts K, Plata C, De Vooght V, Vanoirbeek JAJ, Meseguer VM, Voets T, Alvarez JL, Hellings PW, Hoet PHM, Nemery B, Valverde MA, Talavera K
Nat Commun. 2017
The latest study from the Voets lab shows that LPS activates TRPV4 ion channels on airway epithelial cells. Channel opening leads to an influx of calcium ions, which in a matter of minutes activates a wide range of antimicrobial responses. These include the production of bactericidal nitric oxide and increase of the movement of cilia leading to bacterial clearance. Importantly, this response does not require the classical TLR4 immune signaling cascade. This study establishes these sensory TRP channels as a completely new class of effectors of bacterial cues, and therefore as key players in mechanisms of innate immunity.
HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients
Guo W, Naujock M, Fumagalli L, Vandoorne T, Baatsen P, Boon R, Ordovás L, Patel A, Welters M, Vanwelden T, Geens N, Tricot T, Benoy V, Steyaert J, Lefebvre-Omar C, Boesmans W, Jarpe M, Sterneckert J, Wegner F, Petri S, Bohl D, Vanden Berghe P, Robberecht W, Van Damme P, Verfaillie C, Van Den Bosch L
Nat Commun. 2017
The team of Ludo Van Den Bosch used stem cell technology to generate motor neurons from ALS patients carrying mutations in FUS. They found disturbed axonal transport in these motor neurons, but also identified genetic and pharmacological strategies that mitigate these defects.
SCENIC: single-cell regulatory network inference and clustering
Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, Rambow F, Marine JC, Geurts P, Aerts J, van den Oord J, Atak ZK, Wouters J, Aerts S
Nat Methods. 2017
The team of Stein Aerts presents SCENIC, a computational method for simultaneous gene regulatory network reconstruction and cell-state identification from single-cell RNA-seq data. On a compendium of single-cell data from tumors and brain, they demonstrate that cis-regulatory analysis can be exploited to guide the identification of transcription factors and cell states. As such, SCENIC can provide critical biological insights into the mechanisms driving cellular heterogeneity. More info via scenic.aertslab.org.
Modulation of γ- and β-Secretases as Early Prevention Against Alzheimer’s Disease
Voytyuk I, De Strooper B, Chávez-Gutiérrez L
Biol Psychiatry. 2017
There is a lot of genetic evidence implicating amyloid-beta in the initial stages of Alzheimer’s disease, but the long prodromal phase of the disease suggests that the full story is more complicated. It is unlikely that treatments directed at amyloid-beta will have major clinical effects in the later stages of the disease, but in a new review Iryna Voytyuk from the De Strooper lab discuss data on the two major candidate targets for preventation: gamma- and beta-secretase.
Identification of cis-regulatory mutations generating de novo edges in personalized cancer gene regulatory networks
Kalender Atak Z, Imrichova H, Svetlichnyy D, Hulselmans G, Christiaens V, Reumers J, Ceulemans H, Aerts S
Genome Med. 2017
The Aerts lab introduces μ-cisTarget to filter, annotate and prioritize cis-regulatory mutations based on their putative effect on the underlying “personal” gene regulatory network. They validated μ-cisTarget by re-analyzing the TAL1 and LMO1 enhancer mutations in T-ALL, and the TERT promoter mutation in melanoma. Next, they re-sequenced the full genomes of ten cancer cell lines and used matched transcriptome data and motif discovery to identify master regulators with de novo binding sites that result in the up-regulation of nearby oncogenic drivers.
μ-cisTarget is available from http://mucistarget.aertslab.org.
Abnormal striatal plasticity in a DYT11/SGCE myoclonus dystonia mouse model is reversed by adenosine A2A receptor inhibition
Maltese M, Martella G, Imbriani P, Schuermans J, Billion K, Sciamanna G, Farook F, Ponterio G, Tassone A, Santoro M, Bonsi P, Pisani A, Goodchild RE
Neurobiol Dis. 2017
Striatal dysfunction is implicated in many movement disorders. However, the precise nature of defects often remains uncharacterized, which hinders therapy development. In collaboration with the university of Rome, the Goodchild lab examined striatal function in a mouse model of the incurable movement disorder, myoclonus dystonia, caused by SGCE mutations. They found that Sgce loss specifically inhibits LTD, which implicates this neurophysiological defect in myoclonus dystonia, and emphasizes that neurophysiological changes can occur in the absence of broad striatal dysfunction. Further, they found positive effects using A2AR antagonists, indicating that this drug class could be tested in DYT11/SGCE dystonia.
Noncoding RNAs in neurodegeneration
Salta E, De Strooper B
Nat Rev Neurosci. 2017
Non-protein-coding RNAs (ncRNAs) regulate various molecular processes in the CNS and have been implicated in neurodevelopment and brain ageing, as well as in synapse function and cognitive performance, in both health and disease. ncRNA-mediated processes may be involved in various aspects of the pathogenesis of neurodegenerative disorders. Understanding these events may help to develop novel diagnostic and therapeutic tools. In this review, Evgenia Salta and Bart De Strooper provide an overview of the complex mechanisms that are affected by the diverse ncRNA classes that have been implicated in neurodegeneration.
The non-coding RNA BC1 regulates experience-dependent structural plasticity and learning
Briz V, Restivo L, Pasciuto E, Juczewski K, Mercaldo V, Lo AC, Baatsen P, Gounko NV, Borreca A, Girardi T, Luca R, Nys J, Poorthuis RB, Mansvelder HD, Fisone G, Ammassari-Teule M, Arckens L, Krieger P, Meredith R, Bagni C
Nat Commun. 2017
The brain cytoplasmic (BC1) RNA is a non-coding RNA (ncRNA) involved in neuronal translational control. The Bagni lab (previously at our center) collaborated with the Gounko lab and others to show that BC1 RNA plays a role in experience-dependent plasticity and learning in the mammalian adult neocortex. The findings provide insight into the function of brain ncRNAs regulating synaptic transmission, plasticity and behavior, with potential relevance in the context of intellectual disabilities and psychiatric disorders.
Alzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions
Szaruga M, Munteanu B, Lismont S, Veugelen S, Horré K, Mercken M, Saido TC, Ryan NS, De Vos T, Savvides SN, Gallardo R, Schymkowitz J, Rousseau F, Fox NC, Hopf C, De Strooper B, Chávez-Gutiérrez L
The Chávez-Gutiérrez and De Stooper labs have shown that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential γ-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer Aβ peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic Aβ. In contrast, E-Aβn stabilizers increase γ-secretase processivity. These results suggests that environmental factors may increase AD risk, and provides the theoretical basis for the development of γ-secretase/substrate stabilizing compounds for the prevention of AD.
Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease
Poesen K, De Schaepdryver M, Stubendorff B, Gille B, Muckova P, Wendler S, Prell T, Ringer TM, Rhode H, Stevens O, Claeys KG, Couwelier G, D'Hondt A, Lamaire N, Tilkin P, Van Reijen D, Gourmaud S, Fedtke N, Heiling B, Rumpel M, Rödiger A, Gunkel A, Witte OW, Paquet C, Vandenberghe R, Grosskreutz J, Van Damme P
Philip Van Damme and his team, in collaboration with UZ Leuven and researchers at the University of Jena, has demonstrated that measuring neurofilaments provides reliable confirmation of an ALS diagnosis. They show that pNfH (phosphorylated neurofilament heavy) in particular is sharply increased in the lumbar fluid of ALS patients, even when compared to patients presenting loss of strength symptoms due to other conditions (known as ALS mimics). This diagnostic test represents a significant step forward because valuable time is still lost at present in diagnosing ALS.
Inactivation of γ‐secretases leads to accumulation of substrates and non‐Alzheimer neurodegeneration
Acx H, Serneels L, Radaelli E, Muyldermans S, Vincke C, Pepermans E, Müller U, Chávez‐Gutiérrez L, De Strooper B
EMBO Mol Medicine. 2017
The De Strooper lab made knockouts of the 3 different variants of the Aph1 subunit of gamma-secretase in pyramidal neurons, and found specific neurodegeneration in the combined knockout but not the specific knockouts. These data support the possibility that different gamma-secretases can at least partially compensate for each other’s loss.
Identification and Characterisation of Nanobodies targeting the EphA4 receptor
Schoonaert L, Rué L, Roucourt B, Timmers M, Little S, Chávez Gutiérrez L, Dewilde M1 Joyce P, Curnock A, Weber P, Haustraete J, Hassanzadeh-Ghassabeh G, De Strooper B, Van Den Bosch L, Van Damme P, Lemmens R, Robberecht W
J Biol Chem. 2017
Lies Schoonaert and Laura Rué set out to generate potent and selective Nanobodies against the ligand-binding domain of the human EphA4 receptor, which plays a pivotal role in a variety of cell-cell interactions and is involved in cancer biology as well as in the pathogenesis of several neurological disorders. The team identified two Nanobodies, Nb 39 and Nb 53, that bind EphA4 with affinities in the nanomolar range.
Autophagy in the presynaptic compartment in health and disease
Vijayan V, Verstreken P
Evidence from research on both autophagy and synaptic function suggests that there are links between the two and that synaptic homeostasis during aging requires autophagy to regulate protein homeostasis. Vinoy Vijayan and Patrik Verstreken review exciting new work on autophagy-modulating proteins that are enriched at the synapse and highlight how these findings link autophagy to synapses and synaptic dysfunction in disease.
Tau association with synaptic vesicles causes presynaptic dysfunction
Zhou L, McInnes J, Wierda K, Holt M, Herrmann AG, Jackson RJ, Wang YC, Swerts J, Beyens J, Miskiewicz K, Vilain S, Dewachter I, Moechars D, De Strooper B, Spires-Jones TL, de Wit J, Verstreken P
Nature Communications. 2017
Lujia Zhou and Joe McInnes from the Verstreken lab show that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic functions. Pathological Tau mutants lacking the vesicle binding domain still localize to the presynaptic compartment but do not impair synaptic function in fly neurons. This work uncovers a presynaptic role of Tau that may be part of the early pathology in various Tauopathies and could be exploited therapeutically.
Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo
Beel S, Moisse M, Damme M, De Muynck L, Robberecht W, Van Den Bosch L, Saftig P, Van Damme P
Human Mol Genet. 2017
Sander Beel and Philip Van Damme from the Van Den Bosch lab show that dysfunction of lysosomal enzymes such as cathepsin D can contribute to neuronal dysfunction caused by progranulin deficiency in diseases such as frontotemporal dementia.
Neuronal Polarity: MAP2 Shifts Secretory Vesicles into High Gear for Long-Haul Transport down the Axon
Ribeiro LF, de Wit J
Preview in Neuron. 2017
Accurate control of polarized cargo trafficking is essential for neuronal function. Luis Ribeiro and Joris de Wit wrote a comment on a paper by Gumy et al. (2017), which shows that MAP2 defines a pre-axonal filtering zone and controls axonal cargo transport by influencing the activities of distinct kinesin motors.
Modelling amyotrophic lateral sclerosis: progress and possibilities
Van Damme P, Robberecht W, Van Den Bosch L
Disease Models & Mechanisms. 2017
To date, around 20 genes are associated with ALS, with the most common causes of typical ALS associated with mutations in SOD1, TARDBP, FUS and C9orf72. Advances in our understanding of the genetic basis of ALS have led to the creation of different models of this disease and Philip Van Damme, Wim Robberecht and Ludo Van Den Bosch describe the state of the field.
Alzheimer’s disease: where next for anti-amyloid therapies?
De Strooper B, Hardy J
Guest editorial by Bart De Strooper and John Hardy in Brain on the future of anti-amyloid therapies. They make the case that systematic and open data analysis at all stages of disease investigation will be key if we want to make progress.
An immunoaffinity-based method for isolating ultrapure adult astrocytes based on ATP1B2 targeting by the ACSA-2 antibody
Batiuk MY, de Vin F, Duqué SI, Li C, Saito T, Saido T, Fiers M, Belgard TH, Holt MG
The Holt lab identifies the epitope for the ACSA-2 antibody and demonstrates how the antibody can be used to isolate ultrapure astrocytes from adult brain. They suggest that ACSA-2 should be a first-choice method for astrocyte isolation and characterization.
Prediction and Reduction of the Aggregation of Monoclonal Antibodies
van der Kant R, Karow-Zwick AR, Van Durme J, Blech M, Gallardo R. Seeliger D, Aßfalg K, Baatsen P, Compernolle G, Gils A, Studts JM, Schulz P, Garidel P, Schymkowitz J, Rousseau F
Journal of Molecular Biology. 2017
The Switch lab on how to predict and redesign the solubility of monoclonal antibodies by introducing artificial aggregation gatekeeper residues.
Hallmarks of Alzheimer’s Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain
Espuny-Camacho I, Arranz AM, Fiers M, Snellinx A, Ando K, Munck S, Bonnefont J, Lambot L, Corthout N, Omodho L, Vanden Eynden E, Radaelli E, Tesseur I, Wray S, Ebneth A, Hardy J, Leroy K, Brion JP, Vanderhaeghen P, De Strooper B
The De Strooper lab teamed up with Pierre Vanderhaeghen (ULB and visiting PI at our department) to develop a new chimeric AD model: they transplanted differentiated iPS cells into the brains of AD mice and found degeneration and major loss of human neurons without the presence of Tau tangles. This novel model opens up new ways of studying AD in a human genetic background.
[Think this work is fascinating and want to work with this model yourself? Take a look at our Careers page, the De Strooper lab is hiring!]
Tetraspanin 6: A novel regulator of hippocampal synaptic transmission and long term plasticity
Salas IH, Callaerts-Vegh Z, Arranz AM, Guix FX, D'Hooge R, Esteban JA, De Strooper B, Dotti CG
PLoS ONE. 2017
Tetraspanins are transmembrane proteins with important scaffold and signalling functions. Since Tetraspanin 7 plays a key role in synapse development, Isabel Salas from the De Strooper and Dotti labs explored how of Tetraspanin 6 affects synaptic function using a knock-out mouse model.
Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency
Vos M, Geens A, Böhm C, Deaulmerie L, Swerts J, Rossi M, Craessaerts K, Leites EP, Seibler P, Rakovic A, Lohnau T, De Strooper B, Fendt SM, Morais VA, Klein C, Verstreken P
The Verstreken lab teamed up with several collaborators to show that inhibition of FASN (fatty acid synthase) rescues Parkinson's disease-associated PINK1 deficiency in flies, in mouse cells and in human cells and neurons. Lower FASN activity increases the levels of Cardiolipin (a mitochondrial inner membrane–specific lipid) which rescues PINK1 deficiency by bypassing the complex I defects.
A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics: the case of NPC1 deficiency
Tharkeshwar AK, Trekker J, Vermeire W, Pauwels J, Sannerud R, Priestman DA, Te Vruchte D, Vints K, Baatsen P, Decuypere JP, Lu H, Martin S, Vangheluwe P, Swinnen JV, Lagae L, Impens F, Platt FM, Gevaert K, Annaert W
Sci Rep. 2017
The lab of Wim Annaert engineered superparamagnetic iron oxide nanoparticles (SPIONs) targeting distinct subcellular compartments. They used different types of SPIONs to compare the biomolecular compositions of lysosomes and plasma membranes isolated from wild-type and Niemann-Pick disease type C1 (NPC1) deficient cells, and found disease-related alterations that were location specific. These findings demonstrate how SPIONs can be used to fingerprint sub cellular compartments and identify pathological changes at a much better resolution than in whole cells or tissues.
Decoding transcriptional states in cancer
Wouters J, Kalender Atak Z, Aerts S
Curr Opin Genet Dev. 2017
New algorithms, data integration strategies, and increasing amounts of single-cell genomics data provide exciting opportunities to model dynamic regulatory states at unprecedented resolution. In this review, Jasper Wouters, Zeynep Kalender Atak and Stein Aerts give an overview of recent experimental and computational techniques using transcriptome and epigenome data that can be used to reverse engineer cancer gene networks.
PLD3 gene and APP processing
Fazzari P, Horré K, Arranz AM, Sala Frigerio C, Saito T, Saido TC, De Strooper B
Loss of Phospholipase D3 (PLD3) function has been proposed to increase the risk for Alzheimer’s disease by affecting the processing of the Aβ precursor protein APP. However, researchers at the De Strooper lab have found that PLD3 is not relevant for APP metabolism in wild-type mice or in a mouse model of Alzheimer’s disease pathology. They demonstrated that the PLD3 protein is localized in the lysosomal system and affects its morphology, indicating that PLD3 may be involved in the pathophysiology of Alzheimer’s disease by exacerbating impairments of the endosomal–lysosomal system.
A novel kindred with inherited STAT2 deficiency and severe viral illness
Moens L, Van Eyck L, Jochmans D, Mitera T, Frans G, Bossuyt X, Matthys P, Neyts J, Ciancanelli M, Zhang SY, Gijsbers R, Casanova JL, Boisson-Dupuis S, Meyts I, Liston A
Journal of Allergy and Clinical Immunology. 2017
A team of scientists led by Adrian Liston and Isabelle Meyts (UZ Leuven–KU Leuven) were able to characterize a new genetic immunodeficiency resulting from a mutation in a gene named STAT2. This mutation causes patients to be extremely vulnerable to normally mild childhood illnesses such as rotavirus and enterovirus.