Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia

Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ‘tethering’ proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity

Analysis of plasma enhanced pulsed laser deposition of transition metal oxide thin films using medium energy ion scattering

In this study, plasma-enhanced pulsed laser deposition (PE-PLD), which is a novel variant of pulsed laser deposition that combines laser ablation of metal targets with an electrically-produced oxygen plasma background, has been used for the fabrication of ZnO and Cu2O thin films. Samples prepared using the PE-PLD process, with the aim of generating desirable properties for a range of electrical and optical applications, have been analysed using medium energy ion scattering. Using a 100 keV He+ ion beam, high resolution depth profiling of the films was performed with an analysis of the stoichiometry and interface abruptness of these novel materials. It was found that the PE-PLD process can create stoichiometric thin films, the uniformity of which can be controlled by varying the power of the inductively coupled plasma. This technique showed a high deposition rate of ∼0.1 nm s−1

Properties of µPCVD poly-silicon films after rapid thermal annealing

Polly-Silicon Films obtained by µPCVD were studied with respect to their structural and electrical properties influenced by rapid thermal annealing (RTA) in vacuum. In addition an annealing in H2 atmosphere at atmospheric pressure was curried out. The structure and the morphology of the films were studied by Reflection High Energy Electron Diffraction (RHEED) technique and Scanning Electron Microscopy (SEM), respectively. An effect of increase of the crystallinity of the poly-Si films was observed as a result of RTA annealing. These observations coincide well with the measured sheet resistance of the layers. It was found that sheet resistance of the as-deposited films is about [MATH] and it decreases to a value of about [MATH] in dependence on the annealing

Investigation of the structure of tungsten oxide films obtained by chemical vapor deposition

Thin amorphous and polycrystalline tungsten oxide films have been prepared by Chemical Vapor Deposition (CVD) from metallorganic precursor − tungsten hexacarbonyl − at atmospheric pressure. The dependence of the composition and the structure of tungsten oxide films on the technological conditions has been investigated by XPS, XRD, DTA-TGA and Raman spectroscopy. As a result it has been established that: at high values of the flow-rates of the reaction gases amorphous films of very low density have been obtained; in the XPS spectra of the understoichiometric WO3−y (0 < y < 0.3) films besides W6+, also W5+ and W4+ states have been observed. First to observe in the Raman spectra of amorphous CVD-WO3 films is the band at ~ 950 cm−1, characteristic for terminal W6+ = O bonds in result of the presence of structural water. The existence of structural water in the amorphous material has been established by thermal analyze, also

Vapor growth of electrochromic thin films of transition metal oxides

Mixed oxide films of transition metals gain considerable much attention due to their interesting optoelectronic properties. The low temperature chemical vapor growth processing of thin films of mixed W and Mo oxides is presented. The investigation is related to optimization of films structure and the related optoelectronic properties in dependence on the chemical vapor deposition (CVD) process parameters. Their electrochromic behavior and photoelectrode properties were studied

Plasma enhanced MOCVD of transition metal oxide thin films with a thickness between some hundred and less than one nanometer for optical applications

Ivanova T, Gesheva K, Hamelmann F, Hachmann W, Heinzmann U, Brechling A. Plasma enhanced MOCVD of transition metal oxide thin films with a thickness between some hundred and less than one nanometer for optical applications. In: ECS Proceedings; PV 2005-09. 2005: 433-433

Technology and characterization of CVD-grown mixed Mo/W oxide films and electrochromic devices made on their basis

Gesheva K, Ivanova T, Steinman E, Hamelmann F, Heinzmann U, Brechling A. Technology and characterization of CVD-grown mixed Mo/W oxide films and electrochromic devices made on their basis. In: ECS Proceedings PV 2005-09. 2005: 799-799