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BAG1 stellt die Bildung funktionaler DJ-1-L166P-Dimere und deren Chaperon-Aktivität wieder her

BAG1 restores formation of functional DJ-1 L166P dimers and DJ-1 chaperone activity

by Sebastian Deeg
Cumulative thesis
Date of Examination:2011-01-25
Date of issue:2011-01-18
Advisor:Prof. Dr. Pawel Kermer
Referee:Prof. Dr. Pawel Kermer
Referee:Prof. Dr. Michael Müller
crossref-logoPersistent Address: http://dx.doi.org/10.53846/goediss-913

 

 

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Abstract

English

DJ-1 (PARK7) is the encoded protein from one of the four chromosomal loci associated with autosomal recessive, early onset parkinsonism. While evidence from genetic and biochemical studies in murine and human cell lines indicates a role for DJ-1 as an antioxidant forming a homodimer, the function of DJ-1 still remains controversial. In our study, we demonstrate a protein interaction by co-immunoprecipitation between DJ-1 and BAG1 (Bcl-2-associated athanogene-1), which was found to be a regulator of Hsp70/Hsc70 family molecular chaperones inducing foldase activity in neurons. Moreover, we show that DJ-1/BAG1 protein interaction leads to changes in distribution and localisation of DJ-1 within the cell, which can be presented by a detailed analysis of the subcellular fractionation of DJ-1 and its mutant in the presence or absence of BAG1. Regarding the functional relevance of this interaction, we performed FRET (fluorescence resonance energy transfer) experiments demonstrating a clear increase in DJ-1 dimerization in presence of BAG1. In intact neuronal cells, this increased dimerization resulted in restoration of DJ-1 chaperone function as was shown by a new biosensor for chaperone foldase activity. Taken together, we show for the first time in situ that modulation of the chaperone protein folding machinery leads to a functional restoration of a mutant protein specific for a neurodegenerative disease.
Keywords: Parkinson´s desease; dimerization; refolding; chaperone

Other Languages

DJ-1 (PARK7) ist das Genprodukt von einem der vier bekannten chromosomalen Loci, die mit autosomal-rezessivem Parkinson assoziiert ist. Die Funktion von DJ-1 ist weiterhin unklar. In unserer Arbeit beschreiben wir eine Proteininteraktion mittels Koimmunopräzipitation zwischen DJ-1 und BAG1 (Bcl-2-associated athanogene-1). BAG1 ist als Regulator von Hsp70/Hsc70-Chaperon bekannt und induziert Faltungsaktivität in Neuronen. Desweiteren zeigen wir, das die DJ-1/BAG1 Proteininteraktion zu einer Änderung von Verteilung und Lokalisation von DJ-1 in der Zelle führt. Hinsichtlich der funktionellen Relevanz der Interaktion führten wir FRET (fluorescence resonance energy transfer) -Experimente durch, die einen klaren Anstieg der Dimerisation von DJ-1 in Anwesenheit von BAG-1 zeigten. In intakten neuronalen Zellen konnte mit Hilfe eines neuen Biosensors für Chaperon-Faltungsaktivität eine mögliche Funktion von DJ-1 als molekulares Chaperon beschrieben werden.
Schlagwörter: Parkinson Erkrankung; Dimerisierung; Refaltung; Chaperon
 

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