Suchergebnisse

Copyright: © 2016 Aerts et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ; Mutations in the gene encoding the mitochondrial kinase PINK1 cause early-onset familial Parkinson's disease. To understand the biological function of PINK1 and its role in the pathogenesis of Parkinson's disease, it is useful to study its kinase activity towards substrates both in vivo and in vitro. For in vitro kinase assays, a purified Triboleum castaneum PINK1 insect orthologue is often employed, because it displays higher levels of activity when compared to human PINK1. We show, however, that the activity requirements, and more importantly the substrate specificity, differ between both orthologues. While Triboleum castaneum PINK1 readily phosphorylates the PINKtide peptide and Histone H1 in vitro, neither of these non-physiological substrates is phosphorylated by human PINK1. Nonetheless, both Tc and human PINK1 phosphorylate Parkin and Ubiquitin, two physiological substrates of PINK1. Our results show that the substrate selectivity differs among PINK1 orthologues, an important consideration that should be taken into account when extrapolating findings back to human PINK1. ; This work was supported by the Flemish agency for Innovation by Science and Technology (IWT), the Fund for Scientific Research Flanders (FWO), research fund KU Leuven, the Hercules Foundation, the Federal Office for Scientific Affairs (IAP P7/16), a Methusalem grant of the Flemish Government, and VIB. LA is supported by an IWT doctoral grant. BDS is the Arthur Bax and Anna Vanluffelen chair for Alzheimer's disease. VAM is supported by the Fundação para a Ciência e a Tecnologia (FCT) for the FCT Investigator Grant (IF/01693/2014). BDS is a paid consultant for the Alzheimer's disease research programs at Janssen Pharmaceutica, Envivo, and Remynd NV. ...

In this study, we report the results of a comprehensive phenotyping of the retina of the App(NL-G-F) mouse. We demonstrate that soluble A beta accumulation is present in the retina of these mice early in life and progresses to A beta plaque formation by midlife. This rising A beta burden coincides with local microglia reactivity, astrogliosis, and abnormalities in retinal vein morphology. Electrophysiological recordings revealed signs of neuronal dysfunction yet no overt neurodegeneration was observed and visual performance outcomes were unaffected in the App(NL-G-F) mouse. Furthermore, we show that hyperspectral imaging can be used to quantify retinal A beta, underscoring its potential as a biomarker for AD diagnosis and monitoring. These findings suggest that the App(NL-G-F) retina mimics the early, preclinical stages of AD, and, together with retinal imaging techniques, offers unique opportunities for drug discovery and fundamental research into preclinical AD. ; MV, LV, LuM and LDG are fellows of the Research Foundation Flanders (FWO). This research was supported by the Alzheimer's Research Foundation (SAO-FRA), the European Union Horizon 2020 Research and Innovation Program (2014-2020) (HERALD project, granted by the ATTRAC T consortium). The Centre for Eye Research Australia receives Operational Infrastructure Support from the Victorian Government. XH and PvW acknowledge funding support from the H & L Hecht Trust and the Yulgilbar Alzheimer's Research Program. ; De Groef, L (corresponding author), Univ Leuven KU Leuven, Dept Biol, Neural Circuit Dev & Regenerat Res Grp, Naamsestr 61,Box 2464, B-3000 Leuven, Belgium. Lies.Degroef@kuleuven.be

Tau is implicated in more than 20 neurodegenerative diseases, including Alzheimer's disease. Under pathological conditions, Tau dissociates from axonal microtubules and missorts to pre- and postsynaptic terminals. Patients suffer from early synaptic dysfunction prior to Tau aggregate formation, but the underlying mechanism is unclear. Here we show that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic functions, including synaptic vesicle mobility and release rate, lowering neurotransmission in fly and rat neurons. Pathological Tau mutants lacking the vesicle binding domain still localize to the presynaptic compartment but do not impair synaptic function in fly neurons. Moreover, an exogenously applied membrane-permeable peptide that competes for Tau-vesicle binding suppresses Tau-induced synaptic toxicity in rat neurons. Our work uncovers a presynaptic role of Tau that may be part of the early pathology in various Tauopathies and could be exploited therapeutically. ; We thank Colin Smith and Matthew Frosch for access to human tissue. We thank lab members of the Verstreken laboratory for helpful discussions, and Kristel Vennekens and An Snellinx for technical support. Support was provided by an ERC Starting Grant (260678), ERC Consolidator grant (646671), the Instituut voor Wetenschap en Technologie (IWT O&O grant), the Interuniversity Attraction Pole program by BELSPO, the research fund KU Leuven, a Methusalem grant of the Flemish government and VIB, Leuvens Universiteitsfonds (LUF) Opening the Future grant, and a Belgian-American Educational Foundation fellowship to J.M. T.S.-J., A.H. and R.J.J. receive funding from Alzheimer's Research UK, an anonymous foundation, and a Welcome Trust Institutional strategic support grant.

Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Aβ42 versus Aβ40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects amyloid beta‐peptide (Aβ) generation as well. Here we demonstrate that the secretion of Aβ is enhanced in an in vitro model of neuronal ageing, correlating with an increase in γ‐secretase complex formation. Moreover we found that peroxynitrite (ONOO−), produced by the reaction of superoxide anion with nitric oxide, promoted the nitrotyrosination of presenilin 1 (PS1), the catalytic subunit of γ‐secretase. This was associated with an increased association of the two PS1 fragments, PS1‐CTF and PS1‐NTF, which constitute the active catalytic centre. Furthermore, we found that peroxynitrite shifted the production of Aβ towards Aβ42 and increased the Aβ42/Aβ40 ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD. ; This work was made possible by grants from the Fund for Scientific Research, Flanders; the K.U.Leuven; the VIB, Methusalem (K.U.Leuven and the Flemisch government), the Foundation for Alzheimer Research (SAO/FRMA), the European Research council (BDS), NIH AG15379 (OB), Spanish Ministry of Science and Innovation SAF 2010‐14906, Consolider 2010‐00045 (CGD), Spanish Ministery of Health (Fondo de Investigación Sanitaria‐PI10/00587 and Red HERACLES RD06/0009); The European FEDER Fundings; and Fundació La Marató de TV3 (Catalonia; Spain; no. 100310). We would like to acknowledge the Banc de Teixits Neurologics de l' Hospital Clinic de Barcelona and the Unidad de Neuropatología y Banco de Cerebros of Fundación Hospital Alcorcón for providing the brain samples. BDS is the Arthur Bax and Anna Vanluffelen chair for AD. FG obtained a IEF fellowship of the Marie Curie Actions program in FP7 and a Beatriu de Pinos grant of the Generalitat de Catalunya, Spain. TW was supported by EMBO and DFG long‐term fellowships