<p class="first" id="d1091432e115">Prolyl oligopeptidase (PREP) is a serine protease
that has been studied particularly
in the context of neurodegenerative diseases for decades but its physiological function
has remained unclear. We have previously found that PREP negatively regulates beclin1-mediated
macroautophagy (autophagy), and that PREP inhibition by a small-molecule inhibitor
induces clearance of protein aggregates in Parkinson's disease models. Since autophagy
induction has been suggested as a potential therapy for several diseases, we wanted
to further characterize how PREP regulates autophagy. We measured the levels of various
kinases and proteins regulating beclin1-autophagy in HEK-293 and SH-SY5Y cell cultures
after PREP inhibition, PREP deletion, and PREP overexpression and restoration, and
verified the results in vivo by using PREP knock-out and wild-type mouse tissue where
PREP was restored or overexpressed, respectively. We found that PREP regulates autophagy
by interacting with protein phosphatase 2A (PP2A) and its endogenous inhibitor, protein
phosphatase methylesterase 1 (PME1), and activator (protein phosphatase 2 phosphatase
activator, PTPA), thus adjusting its activity and the levels of PP2A in the intracellular
pool. PREP inhibition and deletion increased PP2A activity, leading to activation
of death-associated protein kinase 1 (DAPK1), beclin1 phosphorylation and induced
autophagy while PREP overexpression reduced this. Lowered activity of PP2A is connected
to several neurodegenerative disorders and cancers, and PP2A activators would have
enormous potential as drug therapy but development of such compounds has been a challenge.
The concept of PREP inhibition has been proved safe, and therefore, our study supports
the further development of PREP inhibitors as PP2A activators.
</p>