المؤلفون: Martin Kiechle, Patrizia Voehringer, Diana Wiesner, Birgit Liss, Rosanna Parlato, Olena Sakk, Bjoern von Einem, Veselin Grozdanov, Albert C. Ludolph, Daniel Markx, Boris Ferger, Lennart Höfs, Pamela J. McLean, Karin M Danzer, Paul Walther, Bernd Baumann, Soeren Lukassen, Jochen H. Weishaupt, Björn H. Falkenburger, Arif B. Ekici, Benjamin Mayer

المصدر: Cell Reports, Vol 29, Iss 9, Pp 2862-2874.e9 (2019)

مصطلحات موضوعية: 0301 basic medicine, Yellow fluorescent protein, Phosphorylierung, animal diseases, Protein combining, PROPAGATION, Mice, chemistry.chemical_compound, DDC 570 / Life sciences, 0302 clinical medicine, PARKINSONS-DISEASE, heterocyclic compounds, Phosphorylation, lcsh:QH301-705.5, Neurons, biology, Chemistry, Neurodegenerative diseases, Neurodegeneration, NEURODEGENERATION, Brain, Synapse, Cell biology, Parkinson disease, alpha-Synuclein, EXPRESSION, Genetically modified mouse, General Biochemistry, Genetics and Molecular Biology, Presynapse, 03 medical and health sciences, Gaussia, ddc:570, Substantia nigra, medicine, Animals, Humans, Parkinson-Krankheit, Luciferase, ddc:610, Synaptic transmission, SYNAPTIC FAILURE, Alpha-synuclein, biology.organism_classification, medicine.disease, DYSFUNCTION, nervous system diseases, Disease Models, Animal, 030104 developmental biology, lcsh:Biology (General), nervous system, health occupations, biology.protein, DDC 610 / Medicine & health, 030217 neurology & neurosurgery

الوصف: Intracellular accumulation of α-synuclein (α-syn) and formation of Lewy bodies are neuropathological characteristics of Parkinson’s disease (PD) and related α-synucleinopathies. Oligomerization and spreading of α-syn from neuron to neuron have been suggested as key events contributing to the progression of PD. To directly visualize and characterize α-syn oligomerization and spreading in vivo, we generated two independent conditional transgenic mouse models based on α-syn protein complementation assays using neuron-specifically expressed split Gaussia luciferase or split Venus yellow fluorescent protein (YFP). These transgenic mice allow direct assessment of the quantity and subcellular distribution of α-syn oligomers in vivo. Using these mouse models, we demonstrate an age-dependent accumulation of a specific subtype of α-syn oligomers. We provide in vivo evidence that, although α-syn is found throughout neurons, α-syn oligomerization takes place at the presynapse. Furthermore, our mouse models provide strong evidence for a transsynaptic cell-to-cell transfer of de novo generated α-syn oligomers in vivo.
publishedVersion

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::09f7eec851a6dda0432a33e23c16134bTest
https://doi.org/10.1016/j.celrep.2019.10.089Test

المؤلفون: Shen Han, Marius Kollmer, Daniel Markx, Stephanie Claus, Paul Walther, Marcus Fändrich

المصدر: Scientific Reports

مصطلحات موضوعية: Amyloid, Electron Microscope Tomography, Amyloid beta-Peptides, Cell Survival, Cell Membrane, Plaque, Amyloid, macromolecular substances, Lipids, Protein Aggregation, Pathological, Article, Protein Aggregates, Alzheimer Disease, Humans, Cells, Cultured

الوصف: The deposition of amyloid fibrils as plaques is a key feature of several neurodegenerative diseases including in particular Alzheimer's. This disease is characterized, if not provoked, by amyloid aggregates formed from Aβ peptide that deposit inside the brain or are toxic to neuronal cells. We here used scanning transmission electron microscopy (STEM) to determine the fibril network structure and interactions of Aβ fibrils within a cell culture model of Alzheimer's disease. STEM images taken from the formed Aβ amyloid deposits revealed three main types of fibril network structures, termed amorphous meshwork, fibril bundle and amyloid star. All three were infiltrated by different types of lipid inclusions from small-sized exosome-like structures (50-100 nm diameter) to large-sized extracellular vesicles (up to 300 nm). The fibrils also presented strong interactions with the surrounding cells such that fibril bundles extended into tubular invaginations of the plasma membrane. Amyloid formation in the cell model was previously found to have an intracellular origin and we show here that it functionally destroys the integrity of the intracellular membranes as it leads to lysosomal leakage. These data provide a mechanistic link to explain why intracellular fibril formation is toxic to the cell.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::8faafa6a7f250db55505485bdceb1bacTest
http://europepmc.org/articles/PMC5327471Test