Quickscan scientific topics 2017

6 December 2017
#Spastic paraplegia #ATP13A2
Scientists of the Albena Jordanova Lab (VIBUAntwerp Center for Molecular Neurology) have identified homozygous mutations in ATP13A2 in families with complicated hereditary spastic paraplegia (HSP).
Biochemical and immunocytochemical assays demonstrated protein instability and abnormal intracellular localization of the mutant proteins. Loss of ATP13A2 function causes a combination of lysosomal and mitochondrial dysfunction that affects multiple neuronal populations. This study expands the clinical spectrum of ATP13A2-associated neurological disorders from HSP to juvenile-onset Parkinsonism.
Estrada-Cuzcano et al., Brain 2017

#Mitochondrial DNA #Genome Architecture #Plant Growth
In addition to the nucleus, mitochondria and chloroplasts in plant cells also contain genomes. Recently, Jonas Blomme of the Dirk Inzé Lab (VIB-UGent Center for Plant Systems Biology) discovered a new protein associated with mitochondrial DNA (mtDNA) in Arabidopsis, namely SWIB5. This protein influences mtDNA architecture and homologous recombination both under normal and genotoxic conditions. Gene expression and mutant phenotypic analysis suggests a link between organellar genome maintenance and cell proliferation.
Blomme et al., Plant Cell 2017

#Tau #Presynaptic function
Lujia Zhou and Joe McInnes of the Patrik Verstreken Lab (VIB-KU Leuven Center for Brain & Disease Research) showed that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic function. Pathological Tau mutants lacking the vesicle binding domain still localize to the presynaptic compartment but do not impair synaptic function in fly neurons. This presynaptic role of Tau may be important in the early phases of pathology in various Tauopathies and could be exploited therapeutically.
Zhou et al., Nature Communications 2017

#Phosphorylation #Aurora #Microtubule bundling
The multiple functions of the highly conserved Aurora kinases are determined by the wide variety of their substrates. Joanna Boruc of the Daniel Van Damme Lab (VIB-UGent Center for Plant Systems Biology) identified the microtubule bundling protein MAP65-1/PRC1/Ase1 as one of the first genuine plant Aurora substrates. Phosphorylation of MAP65-1 by Aurora affects cell division timing in plants via the regulation of its microtubule bundling capacity in concert with other mitotic kinases.
Boruc et al., Plant Physiology 2016

#Y-secretase #Amyloid #Alzheimer
A team led by Lucía Chávez Gutiérrez and Bart De Strooper (VIB-KU Leuven Center for Brain & Disease Research) showed that familial Alzheimer’s disease (AD) mutations in PSEN or APP destabilize the interaction between γ-secretase and APP, thereby promoting the generation of longer Aβ peptides. Similarly, destabilization of complexes by temperature or detergent promotes the release of longer, more amyloidogenic Aβ. This work 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. This research also attracted the attention of our national television.
Szaruga et al., Cell 2017

#N-terminal proteomics #Proteogenomics #Ribosome profiling
Proteogenomics is an emerging interdisciplinary research field where proteomics is used to discover unannotated proteincoding genome regions. Making use of N-terminal proteomic data, together with Petra Van Damme of the Kris Gevaert Lab (VIB-UGent Center for Medical Biotechnology), Patrick Willems of the Frank Van Breusegem Lab (VIB-UGent Center for Plant Systems Biology) reported the discovery of novel proteoforms in Arabidopsis thaliana. By performing ribosome footprinting on the same samples, additional support of translation was obtained. The proposed N-terminal proteogenomic pipeline can facilitate the discovery of translational initiation sites in any genome, thereby aiding genome annotation.
Willems et al., Molecular & Cellular Proteomics 2017

#Alzheimer’s disease #ABCA7 #Nanopore sequencing
The ABCA7 gene is a recently discovered and important risk factor of late-onset Alzheimer’s disease (AD). Particularly protein truncating mutations are directly involved in the pathogenesis. With the use of long-read Oxford Nanopore sequencing, the lab of Kristel Sleegers, part of the Christine Van Broeckhoven research group (VIB-UAntwerp Center for Molecular Neurology) identified novel alternative splicing in ABCA7 mutation carriers. These splicing events have the ability to mitigate the deleterious effects of ABCA7 mutations, which can be potentially harnessed towards a cure of AD.
De Roeck et al., Acta Neuropathol 2017

#Protein-protein interaction #MAPPI-DAT #Data analysis
MAPPI-DAT is an automated data management and analysis software, developed as a collaboration between Surya Gupta of the Lennart Martens Lab and the Jan Tavernier Lab (both of the VIB-UGent Center for Medical Biotechnology). MAPPI-DAT provides an end user-oriented, user-friendly means to handle high-throughput protein-protein interaction data from highly parallel MAPPIT cell microarray experiments. MAPPI-DAT stores
the acquired data alongside the experimental meta data, and automates the processing of this data to obtain a final list of true positive interactors.
Gupta et al., Bioinformatics 2017

#Inflammation #Myocardial Infarction #Dendritic Cells
Peripheral tolerance is crucial for avoiding activation of selfreactive T cells to self-antigens. Sterile tissue injury can break peripheral tolerance, but it is unclear how autoreactive T cells get activated.
Katrien Van der Borght of the Bart Lambrecht and Hamida Hammad Lab (VIB-UGent Center for Inflammation Research) demonstrate that myocardial infarction induces the priming of Th1/Th17 autoreactive CD4+ T cells specific for cardiac selfantigen α-myosin in the heart-draining lymph node through the maturation and migration of conventional dendritic cells type 2 (cDC2). Autoreactive T cell activation may initiate cardiac
autoimmunity and promote adverse cardiac remodeling.
Van der Borght et al., Cell Reports 2017

#Retrosplenial cortex #Hippocampus #Place cell activity
Researchers of the Vincent Bonin Lab (NERF - imec, KU Leuven and VIB) and the McNaughton Lab (Colorado State University) discovered place-cell-like activity in the retrosplenial cortex. Hippocampal place cells (important for spatial memory and navigation) have a sparse firing pattern, which maximizes information storage in memory networks. The retrosplenial cortex is closely connected with the hippocampus and has also been linked to spatial behavior. Combining genetic labeling of cortical neurons and highly sensitive live microscopy, the two areas were found to use similar neural codes, but their activity is driven by distinct environmental/behavioral factors.
Mao et al., Nature Communications 2017

#Bacterial persistence #Structural biology #Toxin-antitoxin modules
Toxin-antitoxin (TA) modules play an important role in the generation of bacterial persister cells, which are tolerant to several classes of antibiotics. While the ccdAB operon on the F plasmid of E. coli is a well-characterized TA module, its autoregulation processes remained poorly understood. Alexandra Vandervelde of the Remy Loris Lab and the Rouslan Efremov Lab (VIB-VUB Center for Structural Biology), together with the Jurij Lah Lab (University of Ljubljana), combined structural biology with biophysics and computational modeling to uncover the molecular mechanism underlying the ratio-dependent transcription regulation of this operon. This involves a unique repressing complex which spirals around the operator.
Vandervelde et al., Nucleic Acids Research, 2017

#Odor localization
José Esquivelzeta Rabell of the Sebastian Haesler Lab (NERF - imec, KU Leuven and VIB) developed a new method to measure the high-frequency respiration that characterizes the sniffing behavior of mice. Using infrared thermography, the team registered inhalation and exhalation patterns in a non-invasive manner and compared what happened when mice were presented with either novel or familiar smells. Mice actively orient their nostrils toward previously unexperienced smells at a remarkable speed: within the very first sniff. The anterior olfactory cortex, the first site of convergence between left and right olfactory inputs, plays a key role in the orientation process.
Esquivelzeta Rabell et al., Current Biology 2017

#Amyloids #Ucleation #Curli
Together with a team, Mike Sleutel of the Han Remaut Lab (VIB-VUB Center for Structural Biology) used a novel microscopy method to examine bacterial amyloid formation in real time. They show that key growth and regulatory characteristics set these functional amyloids apart from the pathological counterparts found in human disease. These insights can inform control mechanisms of pathological amyloids and lead to the development of new biomaterials.
Sleutel et al., Nature Chemical Biology 2017

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