Hard work pays off - eventually, and usually all things happen at the same time. So did also happen in PREP lab as we got 3 publications accepted within a 3 week period.
Firstly, PREP lab MedChem got a paper entitled "Tetrazole as a Replacement of the Electrophilic Group in Characteristic Prolyl Oligopeptidase Inhibitors" accepted to ACS Medicinal Chemistry Letters. This work was first part of Tommi Kilpeläinen's PhD project, and in this study we played a bit with different PREP inhibitor structures, and added tetrazole group as electrophile. The compounds were tested in alpha-synuclein dimerization model, and surprisingly, also part of weak PREP inhibitors reduced alpha-synuclein dimerization. We have already earlier shown that also inactive PREP protein increases alpha-synuclein aggregation, so our finding further supports the fact that PREP inhibitors may do also something else for PREP than just inhibit the proteolytic activity. The study was performed in collaboration with Dr. Maija Lahtela-Kakkonen's modelling team in University of Eastern Finland. Full-text article is available at ACS Medicinal Chemistry Letters website as open acces: https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00394
Second paper was an animal characterization manuscript that got accepted to Scientific Reports. In the publication "Behavioural and dopaminergic changes in double mutated human A30P*A53T alpha-synuclein transgenic mouse model of Parkinson´s disease" performed by Tommi, Ulrika and Reinis, we re-characterized a transgenic double-mutant mouse that is carrying both A30P and A53T point mutated alpha-synuclein. These point mutations in alpha-synuclein gene are associated with increased risk for early-onset Parkinsonism but in earlier reports of this mouse, symptoms started around 12-months of age that is considered aged mouse. However, we took an effort to breed this mouse really a homozygous transgenic mouse, and then symptoms occurred already after 3-months of age, capturing the early-onset Parkinson's phenotype. The paper is open access in Scientific Reports website: https://www.nature.com/articles/s41598-019-54034-z
Finally, the third accepted paper was "Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A" that was accepted to Pharmacological Research. This study took as more than 3 years to complete, and it was mainly performed by Reinis and Maria but basically whole PREP lab took part on the assays. In this paper, we wanted to clarify how PREP regulates cellular recycling system, autophagy. After extensive studies, we found that PREP regulates autophagy (and several other cellular events) by interacting with protein phosphatase 2A (PP2A) and its regulatory network. This is very important finding since PREP inhibition can activate PP2A and lowered PP2A activities are connected to several diseases, including Alzheimer's and Parkinson's diseases and various cancers. Additionally, this finding explains several earlier findings on PREP and PREP inhibitors, and may well be the main physiological function for PREP. Abstract is available at the Pharmacological Research website (https://www.sciencedirect.com/science/article/pii/S1043661819322017?via…) and full-text can be requested from PREP lab.