Publikationsserver der Universitätsbibliothek Marburg

Titel:Wirkungen der natürlich vorkommenden α-Synuclein-Autoantikörper auf toxische α-Synuclein-Fragmente
Autor:Rabenstein, Monika
Weitere Beteiligte: Dodel, R. (Prof. Dr.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0571
DOI: https://doi.org/10.17192/z2014.0571
URN: urn:nbn:de:hebis:04-z2014-05718
DDC: Medizin
Titel (trans.):Effect of Naturally Occurring α-Synuclein-Antibodies on Toxic α-Synuclein-Fragments
Publikationsdatum:2014-08-07
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
α-Synuclein, Parkinson’s Disease, Parkinson-Krankheit, α-Synuclein, Parkinson-Syndrom, naturally occurring autoantibodies, natürlich vorkommende Autoantikörper

Zusammenfassung:
Das idiopathische Parkinson-Syndrom (IPS) gehört zu den häufigsten neurodegenerativen Erkrankungen und trotz intensiver Bemühungen stehen bislang noch keine kausalen Therapiemöglichkeiten zur Verfügung. Lewy-Körperchen, eine der typischen Veränderungen in überlebenden nigralen Neuronen, gelten als pathologische Kennzeichen des IPS. Aggregate von fibrilliertem α-Synuclein (α-Syn), einem aus 140 Aminosäuren (AS) bestehendes Protein, das überwiegend in den präsynaptischen Terminalen von Neuronen im ZNS lokalisiert ist, stellen dabei den Hauptanteil solcher Lewy-Körperchen dar. Kürzlich wurden im Serum von Parkinsonpatienten natürlich vorkommende Autoantikörper gegen humanes α-Syn (nAK α-Syn) nachgewiesen (Papachroni et al., 2007). Solche nAK α-Syn konnten in der Arbeitsgruppe für Neurologische Therapieforschung mittels einer Affinitätssäule aus intravenösen Immunglobulinen (IVIG) isoliert und näher charakterisiert werden. Die physiologische Funktion dieser nAK α-Syn im menschlichen Organismus ist bislang kaum bekannt. Ziel dieser Arbeit war es daher, durch genauere Untersuchung der nAK α-Syn-α-Synuclein-Interaktion eine Grundlage für deren besseres Verständnis und mögliche therapeutische Anwendung zu schaffen. Dafür wurden den einzelnen funktionellen Domänen von α-Syn entsprechende α-Syn-Fragmente verwendet: AS 1-60 (N-terminale Domäne), AS 1-95 (N- terminale Domäne + NAC-Region), AS 61-140 (NAC-Region + C-terminale Domäne), AS 96-140 (C-terminale Domäne) sowie die durch alternatives Spleißen entstehende Deletionsmutante α-Syn 112. Diese α-Syn-Fragmente wurden sowohl frisch als auch 7 Tage gealtert ausgetestet. Erstens sollte untersucht werden, an welche(s) Epitop(e) der α-Syn-Fragmente die nAK α-Syn binden. Dazu wurde das Bindungsverhalten von nAK α-Syn und α-Syn-Fragmenten in Antigen-Antikörper-Bindungsassays mittels ELISA und Dot Blot analysiert. Jedoch konnten weder Epitop(e) für die nAK α-Syn noch ein eindeutiges Bindungsmuster der nAK α-Syn an die einzelnen α-Synuclein-Regionen identifiziert werden. Das unterschiedliche Bindungsverhalten in den hier durchgeführten Bindungsassays scheint auf das gleichzeitige Vorliegen linearer sowie konformationaler Epitope hinzudeuten. Zweitens wurde die Wirkung der α-Synuclein-Fragmente auf die Zellintegrität und mitochondriale Vitalität von primären murinen kortikalen Neuronen und primären murinen Mikroglia in LDH- und MTT-Assay getestet. Bei den α-Syn-Fragmenten 1-95, 61-140 sowie α-Syn 112 konnte eine deutliche proliferationsschädigende Wirkung an neuronalen Zellen im MTT-Assay nachgewiesen werden. Diese zytotoxischen α-Syn-Fragmente wurden dann in einem weiteren Schritt vor Zugabe zu den neuronalen Zellen mit den nAK α-Syn vorinkubiert. Diese hatten auf die α-Syn-Fragmente 1-95 und α-Syn 112 einen neuroprotektiven Einfluss. Dieser Effekt ließ sich allerdings auch durch Vorinkubation der α- Syn-Fragmente mit IVIG beobachten. Drittens wurde untersucht, ob die extrazellulär zugegebenen α-Syn-Fragmente eine Ausschüttung proinflammatorischer Zytokine (TNFα und IL-6) in primären murinen Mikroglia induzieren können. Da dies bei fast allen α-Syn-Fragmenten der Fall war (bis auf 1-60 für IL-6), wurde dann der Einfluss der nAK α-Syn auf die Zytokinausschüttung beurteilt. Durch Vorinkubation mit den nAK α-Syn konnte die α-Syn-Fragment-induzierte TNFα- und IL-6-Ausschüttung deutlich signifikant reduziert werden (bis auf 61-140 für TNFα). Dies weist erstmalig darauf hin, dass die nAK α-Syn einen entscheidenden anti-inflammatorischen Einfluss auf die durch α-Syn ausgelöste Mikrogliaaktivierung haben. Weiterhin scheinen sie zusammen mit IVIG neuroprotektives Potenzial zu besitzen. Die überschiessende Reaktion der Mikroglia spielt eine wichtige Rolle in der Pathogenese des IPS. Daher kann eine modulatorische Beeinflussung der Mikrogliaaktivität, beispielsweise durch Hemmung der Ausschüttung proinflammatorischer Zytokine, einen wichtigen therapeutischen Ansatzpunkt beim IPS darstellen. Für diese Modulation könnten die nAK α-Syn geeignet sein. Für die genauere Überprüfung ihres anti-inflammatorischen Potenzials sind weitere Studien nötig.

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