Prolyl oligopeptidase stimulates the aggregation of alpha-synuclein.
Despite its thorough enzymological and biochemical characterization the exact function of prolyl oligopeptidase (PO, E.C. 3.4.21.26) remains unclear. The positive effect of PO inhibitors on learning and memory in animal models for amnesia, enzyme activity measurements in patient samples and (neuro)peptide degradation studies link the enzyme with neurodegenerative disorders. The brain protein alpha-synuclein currently attracts much attention because of its proposed role in the pathology of Parkinson's disease. A fundamental question concerns how the essentially disordered protein is transformed into the highly organized fibrils that are found in Lewy bodies, the hallmarks of Parkinson's disease. Using gel electrophoresis and MALDI TOF/TOF mass spectrometry we investigated the possibility of alpha-synuclein as a PO substrate. We found that in vitro incubation of the protein with PO did not result in truncation of full-length alpha-synuclein. Surprisingly, however, we found an acceleration of the aggregation process of alpha-synuclein using turbidity measurements that was reversed by specific inhibitors of PO enzymatic activity. If PO displays this activity also in vivo, PO inhibitors might have an effect on neurodegenerative disorders through a decrease in the aggregation of alpha-synuclein.
Laboratory for Medical Biochemistry, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Inger
I
Brandt
Melanie
M
Gérard
Kjell
K
Sergeant
Bart
B
Devreese
Veerle
V
Baekelandt
Koen
K
Augustyns
Simon
S
Scharpé
Yves
Y
Engelborghs
Anne-Marie
AM
Lambeir
D000818:Animals; D006801:Humans; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D000085822:Prolyl Oligopeptidases; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013552:Swine; D051844:alpha-Synuclein / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism
D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D051844:alpha-Synuclein; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D019696:Peptidylprolyl Isomerase