Publikationsserver der Universitätsbibliothek Marburg
Titel:Neurophysiologische Charakterisierung von adulten vulnerablen und resistenten Motoneuronen in einem Mausmodell der Amyotrophen Lateralsklerose
Autor:Fuchs, Andrea
Weitere Beteiligte: Schütz, Burkhard (Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/0174
URN: urn:nbn:de:hebis:04-z2012-01743
DOI: https://doi.org/10.17192/z2012.0174
DDC:610 Medizin
Titel (trans.):Neurophysiological characterization of adult vulnerable and resistant motoneurons in a mouse model of amyotrophic lateral sclerosis
Publikationsdatum:2012-02-16
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Calcium, SOD-1, Amyotrophic lateral sclerosis, Patch clamp, Amyotrophe Lateralsklerose, SOD-1, Motoneuron, Motoneuron, Patch-Clamp-Methode, Calcium

Zusammenfassung:
Die Amyotrophe Lateralsklerose (ALS) ist eine neurodegenerative Erkrankung, die Motoneurone (MN) von Kortex, Hirnstamm und Spinalmark betrifft. Folgen sind Lähmung der Muskulatur und der Tod des Patienten meist innerhalb von drei bis fünf Jahren nach Auftritt der ersten Symptome. Eine wirksame Therapie fehlt. Als gemeinsame finale Ursache der MN-Degeneration bei dieser multifaktoriellen Krankheit werden Übererregbarkeit der Neurone, Calciumüberladung und mitochondriale Schädigung diskutiert. Erregbarkeitseigenschaften und Calciumhomöostase der MN konnten in Mausmodellen der ALS auf Einzelzellebene aus technischen Gründen bisher nur in früh postnatalen (<Postnataltag 10), symptomfreien Tieren untersucht werden. Eine Analyse zu einem Zeitpunkt der Neurodegeneration ist jedoch für eine Ursachenforschung und Therapieentwicklung essentiell. In der vorliegenden Arbeit wurde erstmals im SOD1-G93A ALS-Mausmodell eine umfassende Charakterisierung von adulten MN mittels Whole-Cell Patch-Clamp-Messung und fluorometrischer Analysen des Calciumsignals im akuten Hirnschnitt durchgeführt. Verglichen wurden die Eigenschaften von bei ALS hochvulnerablen MN des Ncl. Hypoglossus (hMN) in Wildtypmäusen und in SOD1-G93A Mäusen im Endstadium der Krankheit. Die höhere Erregbarkeit der SOD1-G93A MN im Vergleich zum Wildtyp in Verbindung mit einem größeren persistierenden Natriumeinwärtsstrom, die in früh postnatalen Tieren beschrieben wurden, konnten in adulten Mäusen nicht beobachtet werden. Bei einer weitestgehend unauffälligen Elektrophysiologie wurde jedoch eine signifikant langsamere Erholung des Calciumsignals im Endstadium der Krankheit aufgedeckt, wenn die Neurone durch elektrische Stimulation mit hohen Calciumkonzentrationen belastet wurden. Bei einer Stimulationsstärke im unteren physiologischen Bereich waren keine Unterschiede zum Wildtyp sichtbar. Ein Vergleich mit den bei ALS resistenten MN des Ncl. Oculomotorius zeigte, dass diese Calciumhomöostasestörung spezifisch für die vulnerablen hMN ist und somit eine Erklärung für die differentielle Vulnerabilität der Neurone liefert. Ursächlich für die Störung war eine Verringerung der mitochondrialen Calciumaufnahme durch Calciumuniporter bei primär konstanter Triebkraft. Dies konnte mittels mitochondrialer Entkopplung, spezifischer pharmakologischer Blockade von Calciumtransportern und fluorometrischer Messung von Calcium- und Rhodamine123-Signalen gezeigt werden. Bei Blockade der Calciumaufnahme in Mitochondrien und in das Endoplasmatische Retikulum konnte außerdem indirekt eine Steigerung der Transportkapazität von Calciumtransportern der Plasmamembran in hMN von SOD1-G93A Mäusen im Endstadium der Krankheit beobachtet werden. Aus den Ergebnissen lässt sich schließen, dass vulnerable MN in dem ALS-Mausmodell eine mitochondriale Störung der Calciumaufnahme durch eine Steigerung des Plasmamembran-Calciumtransportes auszugleichen versuchen. Bei hoher Calciumbelastung jedoch versagt im Endstadium der Krankheit diese Kompensation und eine Calciumüberladung als finale Degenerationsursache von MN bei ALS ist wahrscheinlich.

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