@article{LausserKubisRottbaueretal.2018, author = {Lausser, Ludwig and Kubis, Lea and Rottbauer, Wolfgang and Frank, Derk and Just, Steffen and Kestler, Hans A.}, title = {Semantic Multi-Classifier Systems Identify Predictive Processes in Heart Failure Models across Species}, volume = {8 (2018)}, pages = {158}, journal = {Biomolecules}, number = {4}, publisher = {MDPI}, address = {Basel}, issn = {2218-273X}, doi = {https://doi.org/10.3390/biom8040158}, year = {2018}, abstract = {Genetic model organisms have the potential of removing blind spots from the underlying gene regulatory networks of human diseases. Allowing analyses under experimental conditions they complement the insights gained from observational data. An inevitable requirement for a successful trans-species transfer is an abstract but precise high-level characterization of experimental findings. In this work, we provide a large-scale analysis of seven weak contractility/heart failure genotypes of the model organism zebrafish which all share a weak contractility phenotype. In supervised classification experiments, we screen for discriminative patterns that distinguish between observable phenotypes (homozygous mutant individuals) as well as wild-type (homozygous wild-types) and carriers (heterozygous individuals). As the method of choice we use semantic multi-classifier systems, a knowledge-based approach which constructs hypotheses from a predefined vocabulary of high-level terms (e.g., Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways or Gene Ontology (GO) terms). Evaluating these models leads to a compact description of the underlying processes and guides the screening for new molecular markers of heart failure. Furthermore, we were able to independently corroborate the identified processes in Wistar rats.}, language = {en} } @article{KustermannMantaPaoneetal.2018, author = {Kustermann, Monika and Manta, Linda and Paone, Christoph and Kustermann, Jochen and Lausser, Ludwig and Wiesner, Cora and Eichinger, Ludwig and Clemen, Christoph S. and Schr{\"o}der, Rolf and Kestler, Hans A. and Sandri, Marco and Rottbauer, Wolfgang and Just, Steffen}, title = {Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo}, volume = {14 (2018)}, journal = {Autophagy}, number = {11}, publisher = {Taylor \& Francis}, address = {London}, issn = {1554-8627}, doi = {https://doi.org/10.1080/15548627.2018.1491491}, pages = {1911 -- 1927}, year = {2018}, abstract = {VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio). We found that targeted inactivation of either Vcp or Washc4, led to progressive impairment of cardiac and skeletal muscle function, structure and cytoarchitecture without interfering with the differentiation of both organ systems. Notably, loss of Vcp resulted in compromised protein degradation via the proteasome and the macroautophagy/autophagy machinery, whereas Washc4 deficiency did not affect the function of the ubiquitin-proteasome system (UPS) but caused ER stress and interfered with autophagy function in vivo. In summary, our findings provide novel insights into the in vivo functions of Vcp and its novel interactor Washc4 and their particular and distinct roles during proteostasis in striated muscle cells.}, language = {en} }