Pmr1p: a mediator of alpha-Synuclein-induced cytotoxicity / Stefan Benke
Verfasser/ VerfasserinBenke, Stefan
Begutachter / BegutachterinMadeo Frank
Umfang104 Bl. : 2 Zsfssungen ; Ill., graph. Darst.
HochschulschriftGraz, Univ., Masterarb., 2013
Zsfassung in dt. und engl. Sprache
Schlagwörter (GND)Parkinson-Krankheit / Synucleine / Proteinfaltung / Parkinson-Krankheit / Synucleine / Proteinfaltung / Online-Publikation
URNurn:nbn:at:at-ubg:1-47924 Persistent Identifier (URN)
 Das Werk ist frei verfügbar
Pmr1p: a mediator of alpha-Synuclein-induced cytotoxicity [16.33 mb]
Zusammenfassung (Deutsch)

Morbus Parkinson ist die zweithäufigste neurodegenerative Erkrankung. ?-Synuclein (?-Syn), ein kleines, an sich ungefaltetes Protein größtenteils unbekannter Funktion, nimmt eine zentrale Rolle in der Pathophysiologie von Morbus Parkinson ein. Punktmutationen im Gen das für ?-Syn codiert, sowie die Multiplikation des wildtyp-Gens, können erbliche Formen von Morbus Parkinson auslösen.Mehrere Studien deuten darauf hin, dass fehlgefaltetes ?-Syn den Ca2+-Haushalt in Neuronen stört. Um diese Hypothese zu überprüfen verwendete ich die Bäckerhefe extit Verständnis von Morbus Parkinson beitragen wird.

Zusammenfassung (Englisch)

Parkinson's disease (PD) is the second most common neurodegenerative disease. ?-Synuclein (?Syn), a small, intrinsically unfolded protein of mostly unknown function, which is commonly expressed in the central nervous system, is crucially involved in PD pathophysiology. Point mutations in the gene encoding ?Syn, as well as multiplication of the wild type gene, trigger hereditary forms of PD.It has been suggested that ?Syn toxicity might be based on deregulation of Ca2+ homeostasis. I tried to test this hypothesis using the Bakers yeast Saccharomyces cerevisiae as a model organism. Heterologously expressed in yeast, ?Syn leads to decreased lifespan and increased markers of cellular death, and substantially increased levels of cytoplasmic Ca2+.In order to study the interrelations of Ca2+ homeostasis and ?-Syn pathobiology, I screened deletion mutants of several genes encoding different Ca2+ transporter proteins, that heterologously expressed ?-Syn. These proteins included the high affinity P-type Ca2+/Mn2+ ATPase Pmr1p (located in the Golgi) among other Ca2+ pumps and channels localized in different organelles. I assessed toxicity by measuring known markers of cell death (accumulation of reactive oxygen species, phosphatidylserine externalization, loss of plasma membrane integrity and survival), in addition to measuring cytosolic Ca2+ concentrations using a photoluminescence-based assay.I could show that deletion of the gene coding for the protein Pmr1p drastically decreases ?Syn induced toxicity compared to wildytpe yeast. Interestingly, the PMR1 deletion mutant shows substantially increased cytosolic Ca2+ levels per se, which were not increased any further by ?-Syn. This data indicates that Pmr1p is necessary for ?-Syn induced deregulation of Ca2+ homeostasis and subsequent cell death.As a conclusion, I identified Pmr1p as a mediator of ?-Syn induced toxicity, which will hopefully aid in further understanding the mechanisms underlying Parkinson?s disease.