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:610 Medizin
Publikationsdatum:2014-08-07
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

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

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.

Summary:
The idiopathic Parkinson’s Disease (PD) is a very common neurodegenerative disorder. There is no causal treatment available so far. Lewy bodies, the characteristic feature in surviving nigral neurons, are one of the pathologic hallmarks in PD. Aggregates of fibrillated α-Synuclein (α-Syn), a 140 amino-acids-long protein that is mainly expressed at presynaptic terminals in the CNS, are the major components of Lewy bodies. Recently, natural occurring autoantibodies against α-Syn (nAB α-Syn) were de- tected in the peripheral blood of PD patients and controls (Papachroni et al., 2007). In our group, we affinity-purified nABs α-Syn from intravenous immuno- globulins (IVIG) for further characterization. Since the physiological function of the nAB α-Syn in the human organism is still poorly known, the aim of this project was to specify the interaction of the nABs α-Syn with α-Syn-fragments for providing better understanding and possible treatment application of the nABs α-Syn. This was tested with truncated α-Syn-fragments representing the functional regions of the protein: residues 1-60 (N-terminal domain), residues 1-95 (N- terminal domain + NAC-region), residues 61-140 (NAC-region + C-terminal domain), residues 96-140 (C-terminal domain) and NACP112 (alternative splicing-induced deletion variant lacking amino acids 103-130). The fragments were either freshly prepared or aged for 7 days. First, the epitop(s) on α-Syn for the nAB α-Syn should to be determined. Therefore, binding properties of nAB α-Syn and α-Syn-fragments were analysed in antigen-antibody-binding-assays such as ELISA and Dot Blot. However, neither epitopes for the nAB α-Syn nor clear binding characteristics of the nAB α-Syn to the α-Syn-fragment regions could be identified. The differing binding properties in the assays points to the coexistence of linear and conformational epitopes. Second, the influence of the α-Syn-fragments on cell integrity and viability was tested on primary murine cortical neurons and primary murine microglia using LDH- and MTT-assays. The fragments 1-95, 61-140 and α-Syn 112 decreased cell viability in the primary neuronal culture as measured by MTT-assay. These cytotoxic α-Syn-fragments were subsequently preincubated with the nAB α-Syn-fragments and then added to the primary neuronal culture. There was a rescue effect on the α-Syn-fragments 1-95 and α-Syn 112 as shown by increased cell viabilty. Though, the same rescue effect was attained by preincubation with IVIG. Third, α-Syn-fragments added extracellularly to a primary murine micoglia culture were compared in their ability to induce the release of the proin- flammatory cytokines (TNFα and IL-6). Nearly all α-Syn-fragments (except for 1-60 for IL-6) induced the release of these two cytokines. Subsequently, the impact of the nAB α-Syn on the cytokine realease was determined. There was a highly significant reduction of the TNFα- and IL-6 release by preincubation with the nAB α-Syn (except for 61-140 for TNFα). These results underline for the first time the possible anti-inflammatory effect of the nAB α-Syn on α-Syn-induced microglia activation. Furthermore the findings point to a possible neuroprotective potential for the nAB α-Syn and similarly for IVIG. The overactivation of microglia is an important pathomechanism in PD. Modulating the microglia activity, for example by blocking the release of proinflammatory cytokines with the nAB α-Syn, may therefore provide an important therapeutic target. Further research has to be carried out for the exploration of the nAB α-Syn anti-inflammatory potential.

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