Abbildung 1: PrP-Typisierung nach Proteinase-K-Verdau im Western Blot. ... 9 Abbildung 2: Schematische Struktur des Prion-Proteins. ... 12 Abbildung 3: Umwandlung des Prions von einer α-Helix-Konformation beim PrPC zur β-Faltblattstruktur beim PrPSc. ... 15 Abbildung 4: Limitierter Proteinase-K-Verdau mit anschließendem Western Blot von sCJK- und Kontrollproben... 25 Abbildung 5: Schematische Darstellung des Prion-Proteins mit Bindungsstellen PrP-spezifischer Antikörper. ... 26 Abbildung 6: 2D-Western-Blot-Analyse mit den an die Octarepeat-Region bindenden spezifischen PrP-Antikörpern 3B5 und SAF32. ... 27 Abbildung 7: 2D-Western Blot Analyse mit dem an die Zentral-Region bindenden
PrP-spezifischen Antikörper 3F4. ... 28 Abbildung 8: 2D-Western Blot Analyse von PrPC-Isoformen mit den, gegen die
Kern-Region gerichteten, PrP-spezifischen Antikörpern 12F10 und SAF70. ... 29 Abbildung 9: Zusätzliche fragmentierte PrP-Isoformen in Liquorproben von Patienten mit sCJK und Kontrollen im 2D-Western Blot mit dem PrP-spezifischen Antikörper 12F10. ... 29 Abbildung 10: Statistische Auswertung der unfragmentierten und fragmentierten PrPC
-Isoformen in der 2D-Gelelektrophorese mit dem PrP-spezifischen Antikörper 12F10 ... 30 Abbildung 11: Einfluss des Geschlechts bei CJK-Patienten auf die prozentuale Zusammensetzung einzelner PrPC-Isoformen. ... 31 Abbildung 12: Einfluss des Patientenalters auf prozentuale Anteile einzelner
PrPC-Isoformen. ... 32 Abbildung 13: Vergleich der Isoform Zusammensetzung aus Liquorproben von Patienten mit unterschiedlichem Codon-129-Genotyp (MM, MV, VV) mittels des
Abbildung 15: Vergleich der Isoform Zusammensetzung von Patienten mit bekanntem PRNP-Genotyp (MM, MV, VV an Codon-129) in der 2D-Gelelektrophorese mit dem PrP-spezifischen Antikörper 3F4... 36 Abbildung 16: Statistische Auswertung einzelner PrPC-Isoformen bei bekanntem
PRNP-Genotyp (MM, MV oder VV) nach 2D-Western Blot mit dem PrP-spezifischen Antikörper 3F4. ... 38 Abbildung 17: Vergleich von PrPC-Isoformen aus Liquorproben von Kontroll-Patienten mit definiertem PRNP-Genotyp (MM, MV, VV an Codon-129) in der 2D-Gelelektrophorese mit dem PrP-spezifischen Antikörper SAF32.. ... 39 Abbildung 18: Statistische Auswertung der 2D-Gelelektrophorese von
Kontroll-Patienten mit definiertem Genotyp an Codon-129. ... 41 Abbildung 19: Vergleich der Isoform-Zusammensetzung zwischen PrPSc-Typ 1 und PrPSc-Typ 2 in der 2D -Gelelektrophorese mit dem PrP-spezifischen Antikörper SAF32. ... 42 Abbildung 20: Statistische Auswertung der einzelnen PrP-Isoformen bei PrP-Typ 1 und PrP-Typ 2 im 2D -Western Blot. ... 43 Abbildung 21: Vergleich des Ladungs-Isoform-Profils von VV1 und VV2 in der
2D-Gelelektrophorese mittels des PrP-spezifischen Antikörpers SAF32. ... 44 Abbildung 22: Vergleich der PrPC-Isoform-Zusammensetzung im Liquor von Patienten mit sCJK, fCJK (E200K Mutation), und FFI mittels SAF32. ... 45 Abbildung 23: Statistische Auswertung der 2D-Western Blot Analyse bei sCJK, fCJK und FFI-Patienten. ... 47 Abbildung 24: Immunoblot mittels Ser43 P-PrP in Liquorproben von sCJK und
Kontroll-Patienten. ... 48 Abbildung 25: Immunoblot mittels Ser43 P-PrP in Liquorproben von fCJK (E200K) und Kontroll-Patienten. ... 49 Abbildung 26: Detektion von PrPC-Isoformen mittels des P-PrP Ser43 Antikörpers in Kontroll und CJK-Liquorproben im 2D-Western Blot. ... 49 Abbildung 27: Alpha- und Beta-Cleavage des Prion Proteins in der Übersicht. ... 52
7 Tabellenverzeichnis
Tabelle 1: Übersicht über Erkrankungsalter, einzelne neurologische Symptome und
mediane Überlebenszeit bei sporadischer, familiärer und new variant CJK ... 6
Tabelle 2: Klinische und apparative Diagnosekriterien und Leitfaden zur Klassifizierung einer sCJK ... 7
Tabelle 3: Verteilung des Genotyps an Codon-129 bei sCJK ... 10
Tabelle 4: Verteilung des Genotyps an Codon-129 in der Normalbevölkerung ... 11
Tabelle 5: Übersicht über die benutzten PrP-spezifischen Antikörper ... 19
Tabelle 6: zeitlicher Ablauf der Isofokussierung ... 22
Tabelle 7: Zeitlicher Ablauf des Immunoblots ... 24
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