Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity.

Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins.

Diagnostic accuracy of interleukin-6 for early-onset sepsis in preterm neonates.

Background: Early-onset sepsis (EOS) is a leading cause of morbidity and mortality among neonates. Yet, accurate diagnosis remains a major challenge in clinical routine.Objective: The aim of this study was to evaluate the diagnostic accuracy of Interleukin-6 (IL-6) in combination with other objective perinatal data for early-onset sepsis (EOS) in preterm neonates.Methods: We conducted a retrospective nested case-control study with preterm neonates with a birth weight < 2000 g born in our NICU between January 2007 and June 2016. Differences of IL-6 levels and other perinatal clinical and laboratory data between neonates with and without EOS were statistically analyzed.Results: Sixty-seven preterm infants with and 115 neonates without EOS were included in this study. Specificity and sensitivity for IL-6 were 72.8% and 75.0%, respectively, with an area under the curve of 0.804 at a cut-off point of 40 ng/l. Depending on the statistical method applied, combining IL-6 with a second perinatal factor led either to an increase of specificity (82.4-100%) or sensitivity (75.0-92.2%).Conclusion: The combination of IL-6 with other perinatal factors can significantly increase specificity and sensitivity in the diagnosis of EOS. However, overall diagnostic accuracy cannot be notably improved as there is a tradeoff between sensitivity and specificity. Although these findings do not necessarily apply in clinical routine, they can be of substantial value in the assistance of individual decision making.

Functional characterisation of human synaptic genes expressed in the Drosophila brain.

Drosophila melanogaster is an established and versatile model organism. Here we describe and make available a collection of transgenic Drosophila strains expressing human synaptic genes. The collection can be used to study and characterise human synaptic genes and their interactions and as controls for mutant studies. It was generated in a way that allows the easy addition of new strains, as well as their combination. In order to highlight the potential value of the collection for the characterisation of human synaptic genes we also use two assays, investigating any gain-of-function motor and/or cognitive phenotypes in the strains in this collection. Using these assays we show that among the strains made there are both types of gain-of-function phenotypes investigated. As an example, we focus on the three strains expressing human tyrosine protein kinase Fyn, the small GTPase Rap1a and human Arc, respectively. Of the three, the first shows a cognitive gain-of-function phenotype while the second a motor gain-of-function phenotype. By contrast, Arc, which has no Drosophila ortholog, shows no gain-of-function phenotype.