Prolyl oligopeptidase inhibition reduces PolyQ aggregation and improves cell viability in cellular model of Huntington's disease.

Abstract

Unlike several other neurodegenerative diseases, Huntington's disease (HD) has clear genetic background where huntingtin gene (HTT) has an abnormally expanded CAG repeat near the N terminus. This causes production of mutant huntingtin (mHtt) protein with polyglutamine‐expanded (polyQ) tail, and over 36 CAG repeats cause aggregation‐prone polyQ tail. This leads to accumulation of intracellular aggregates of mHtt in the cell producing toxicity with deleterious effects on gene transcription, protein processing and cell signalling cascades ultimately leading to neuronal death (for review, see Ref.1). Clinically, HD is characterized by severe symptoms such as impaired movement and chorea as well as declined cognitive, and there are currently no rational treatments. Recently, great interests have been devoted to the possibility to reduce mHtt burden by lowering the expression levels of mHtt using DNA‐ or RNA‐targeted therapies. However, these approaches are in their infancy and may bear risks related to complete loss of Htt that may have toxic effects.2 An alternative way to interfere with the aggregates would be to increase the degradation rate of mHtt. As a background to this is the finding that mHtt aggregates are known to impair the ubiquitin‐proteasome system causing a further increase in the intracellular protein load in cells. In addition, autophagy inducers can produce beneficial effects in cell culture and animal models of HD (for review, see Ref.3). However, the potential toxicity and adverse effects of such autophagy inducers may also cause serious drawbacks that has to be taken into account.4 Prolyl oligopeptidase (PREP) is mainly cytosolic enzyme involved in peptide bond cleavage that was recently shown to negatively regulate autophagy.5 KYP‐2047 is a small‐molecule inhibitor of PREP having a disease‐modifying effect in the alpha‐synuclein (aSyn) models of Parkinson´s disease (for review, see Ref.6). We have shown that KYP‐2047 reduced the amount of aSyn‐aggregates in in vitro and in vivo by activating autophagy, while PREP directly interacts with aSyn and colocalizes with aSyn in Parkinsonian brain.6, 7 Interestingly, we observed that PREP is also expressed in the striatum and particularly in the medium spiny neurons8 that preferentially degenerate in HD.1 This prompted us to study whether the inhibition of PREP could interfere with mHtt and reduce its aggregation in cell models of HD.