A Cellular Screening Pattern for Small-Molecular Compounds Targeting Toxic Mechanisms in Parkinson's Disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease, and similar to other neurodegenerative diseases, its treatment is symptomatic. There is a huge need for a disease-modifying therapy but so far, clinical trials aiming for disease-modifying effects have failed. Our earlier studies have shown that modulation of prolyl oligopeptidase (PREP) by small-molecular ligands has beneficial effects on several toxic features seen in PD, such as alpha-synuclein (aSyn) aggregation and degradation via autophagy, and oxidative stress. Based on this, we have developed a cellular screening pattern mimicking several toxic features seen in PD; aSyn dimerization, autophagic flux and production of reactive oxygen species (ROS). We tested two PREP ligands, KYP-2047 and HUP-28, and Anle138b, Nilotinib and Deferiprone, small-molecular compounds currently in clinical trials for PD, in our screening pattern, and validated the results in PD cellular models based on aSyn overexpression and oxidative stress or proteasomal inhibition.  Our results showed that HUP-28 and KYP-2047 that had beneficial effects on more than one toxic mechanism in the cellular screening pattern, had protective effects in PD cellular models. Interestingly, the cellular protection did not correlate with reduced soluble aSyn oligomers that are considered as the toxic species of aSyn.

Note:
Funding Information: The studies were supported by grants from Academy of Finland (318327), Sigrid Juselius Foundation and Business Finland (5609/31/18) for TTM.

Declaration of Interests: None.

Keywords: alpha-synuclein, autophagy, oxidative stress, c-Abl kinase inhibitor, oligomerization inhibitor, iron chelator