Proteasomal stimulation by MK886 and its derivatives can rescue tau-induced neurite pathology

Abstract

Abstract Proteasomal degradation of intrinsically disordered proteins, such as tau, is a critical component of proteostasis in both ageing and neurodegenerative diseases. In this study, we investigated proteasomal activation by MK886 (MK). We previously identified MK as a lead compound capable of modulating tau oligomerization in a cellular FRET assay and rescuing P301L tau-induced cytotoxicity. We first confirmed a robust proteasomal activation by MK using a cellular proteasomal tau-GFP cleavage assay. We then show that MK treatment can significantly rescue tau-induced neurite pathology in differentiated SHSY5Y neurospheres. Due to this compelling result, we designed a series of seven MK analogs to determine if proteasomal activity is sensitive to structural permutations. Using a combination of proteasome, tau aggregation, neurite outgrowth, inflammation, and autophagy assays, we identified two essential substituents of MK that are required for compound activity: 1) Removal of the N-chlorobenzyl group from MK negated both proteasomal and autophagic activity and reduced neurite outgrowth; and 2) removal of the indole-5-isopropyl group significantly improved neurite outgrowth and autophagy activity but reduced its anti-inflammatory capacity. Overall, our results suggest that the combination of proteasomal/autophagic stimulation and anti-inflammatory properties of MK and its derivatives can decrease tau-tau interactions and help rebalance dysfunctional proteostasis. Further development of MK to optimize its proteasomal, autophagic, and anti-inflammatory targets may lead to a novel therapeutic that would be beneficial in ageing and neurodegenerative diseases.