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Prolyl Endopeptidase-Like Facilitates the α-Synuclein Aggregation Seeding, and This Effect Is Reverted by Serine Peptidase Inhibitor PMSF

1
Department of Biophisics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil
2
Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(6), 962; https://doi.org/10.3390/biom10060962
Received: 30 April 2020 / Revised: 16 June 2020 / Accepted: 23 June 2020 / Published: 25 June 2020
The aggregation of α-synuclein (α-Syn) is a characteristic of Parkinson’s disease (PD). α-Syn oligomerization/aggregation is accelerated by the serine peptidase, prolyl oligopeptidase (POP). Factors that affect POP conformation, including most of its inhibitors and an impairing mutation in its active site, influence the acceleration of α-Syn aggregation resulting from the interaction of these proteins. It is noteworthy, however, that α-Syn is not cleaved by POP. Prolyl endopeptidase-like (PREPL) protein is structurally related to the serine peptidases belonging to the POP family. Based on the α-Syn–POP studies and knowing that PREPL may contribute to the regulation of synaptic vesicle exocytosis, when this protein can encounter α-Syn, we investigated the α-Syn–PREPL interaction. The binding of these two human proteins was observed with an apparent affinity constant of about 5.7 μM and, as in the α-Syn assays with POP, the presence of PREPL accelerated the oligomerization/aggregation events, with no α-Syn cleavage. Furthermore, despite this lack of hydrolytic cleavage, the serine peptidase active site inhibitor phenylmethylsulfonyl fluoride (PMSF) abolished the enhancement of the α-Syn aggregation by PREPL. Therefore, given the attention to POP inhibitors as potential drugs to treat synucleinopathies, the present data point to PREPL as another potential target to be explored for this purpose. View Full-Text
Keywords: lewy body; amyloid fibrils; proteolysis lewy body; amyloid fibrils; proteolysis
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Santos, G.S.; Oyadomari, W.Y.; Carvalho, E.A.; Torquato, R.S.; Oliveira, V. Prolyl Endopeptidase-Like Facilitates the α-Synuclein Aggregation Seeding, and This Effect Is Reverted by Serine Peptidase Inhibitor PMSF. Biomolecules 2020, 10, 962.

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