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Proteasomal Stimulation by MK886 and Its Derivatives Can Rescue Tau-Induced Neurite Pathology
Elly E Liao1, Mu Yang1, Noah Nathan Kochen1
1Dept. of Biomedical Engineering, University of Minnesota, Minneapolis, MN, 55455, USA.
Abstract:
Proteasomal degradation of intrinsically disordered proteins, such as tau, is a critical component of proteostasis in both aging 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 robust proteasomal activation by MK using 20S proteasomal assays and 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 the proteasome as the primary MOA, we examined tau aggregation, neurite outgrowth, inflammation, and autophagy assays to identify 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 aging and neurodegenerative diseases.
Insights
MK886 (MK) activates the proteasome, improving cellular proteostasis and rescuing tau-induced neurodegeneration. Analogs reveal key structural elements for optimizing proteasomal, autophagic, and anti-inflammatory activities for potential therapeutic development.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Proteasomal degradation of intrinsically disordered proteins, like tau, is crucial for maintaining proteostasis, especially in aging and neurodegenerative diseases.
- Dysfunctional proteostasis and tau pathology are hallmarks of neurodegenerative conditions.
- MK886 (MK) was previously identified as a compound that modulates tau oligomerization and rescues tau-induced cytotoxicity.
Purpose of the Study:
- To investigate the proteasomal activation by MK886 (MK).
- To assess the therapeutic potential of MK and its analogs in tauopathies.
- To identify key structural features of MK essential for its biological activity.
Main Methods:
- In vitro 20S proteasomal assays and cellular tau-GFP cleavage assays were used to confirm proteasomal activation by MK.
- SHSY5Y neurospheres were utilized to evaluate MK's ability to rescue tau-induced neurite pathology.
- Structure-activity relationship studies were performed on seven MK analogs, assessing tau aggregation, neurite outgrowth, inflammation, and autophagy.
Main Results:
- MK robustly activated proteasomal activity in vitro and in cellular models.
- MK treatment significantly rescued tau-induced neurite pathology in differentiated neurospheres.
- Structural modifications of MK identified essential substituents for proteasomal, autophagic, and anti-inflammatory activities, impacting neurite outgrowth and inflammation.
Conclusions:
- MK886 (MK) demonstrates significant potential as a therapeutic agent by activating the proteasome and mitigating tau pathology.
- The combined proteasomal and autophagic stimulation, along with anti-inflammatory properties, contributes to decreasing tau interactions and rebalancing proteostasis.
- Further optimization of MK analogs could lead to novel therapeutics for aging and neurodegenerative diseases by targeting proteasomal, autophagic, and inflammatory pathways.
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