Zusammenfassung
Humane Typ-1 Porin/VDAC (voltage dependent anion channel)-Kanäle enthalten in ihren N-terminalen Abschnitten, die das β-barrel vom Zellinneren nach der Zellaußenseite hin durchqueren, ein GxxxG-Motiv. Die bei Alzheimer-Kranken stets nachweisbaren pathogenen Amyloidpeptide Aβ1-42 and Aβ1-40 zeigen in der Nähe ihres jeweiligen C-Terminus eine Serie entsprechender Motive. GxxxG-Motive sind als Aggregations- bzw. Membran-irritierende Motive ausgewiesen. Auf diesen Primärstrukturdaten gründet ein Vorschlag, den ich aus der Synopsis aktueller Literatur abgeleitet habe. Danach könnten Aβ-Peptide, die durch die Einwirkung von beta- und gamma-Secretasen aus APP entstehen, bei hypometabolen neuronalen Zellen zur Apoptose führen, indem diese plasmalemmständige Typ-1-Porin/VDAC-Kanäle öffnen. Die Akkumulation solcher Einzelvorgänge mag schließlich zum dem im höheren Lebensalter auftretenden Erscheinungsbild der Alzheimer'schen Erkrankung führen. Bedenkt man das ubiquitäre Auftreten von APP, beta- und gamma-Sekretase wie auch von VDAC, so könnte damit auch ein Hinweis auf einen grundlegenden Apoptosemechanismus gewonnen sein.
Summary
Human type-1 porin/VDAC (voltage-dependent anion channel) carries a GxxxG motif in its N-terminal part, traversing the β-barrel, while the Alzheimer's disease (AD) relevant amyloid peptides Aβ1-42 and Aβ1-40 show a series of corresponding motifs close to their C-terminus. GxxxG motifs are established as aggregation/membrane perturbation motifs. These peptide primary structure data support a proposal I recently made on the basis of a synopsis of recent literature. Accordingly, amyloid Aβ, cut from APP by beta-secretase BACE1 and gamma-secretase, has been insinuated to induce Alzheimer's disease via apoptosis by opening type-1 porin/VDAC in cell membranes of hypometabolic neuronal cells. Considering the ubiquitous expression modus of APP, beta- and gamma-secretases and type-1 VDAC/eukaryotic porin a basic model of apoptosis might be given.
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*Dedicated to Profs. Drs. Hilde Götz and Norbert Hilschmann, Max-Planck-Institut für Experimentelle Medizin, Göttingen, Deutschland.
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Thinnes, F. Apoptogenic interactions of plasmalemmal type-1 VDAC and Aβ peptides via GxxxG motifs induce Alzheimer's disease – a basic model of apoptosis?* . Wien Med Wochenschr 161, 274–276 (2011). https://doi.org/10.1007/s10354-011-0887-5
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DOI: https://doi.org/10.1007/s10354-011-0887-5