Proteasomal Stimulation by MK886 and Its Derivatives Can Rescue Tau-Induced Neurite Pathology

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.