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

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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.

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Data Availability

The datasets generated and/or analyzed during the current study are available upon request.

Abbreviations

Aβ:

amyloid-beta

AD:

Alzheimer’s disease

BafA:

Bafilomycin A1

BTZ:

Bortezomib

EV:

empty vector

5-LO:

5-lipoxygenase

FLAP:

5-lipoxygenase-activating protein

FLT:

fluorescence lifetime

FLT-FRET:

Fluorescence LifeTime-Förster Resonance Energy Transfer

IDP:

intrinsically disordered protein

MK:

MK-886

MOA:

mechanism of action

SHNS:

SHSY5Y neurosphere

WT:

wildtype

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Acknowledgements

We thank Noboru Mizushima for his generous gift (pMRX-IP-GFP-LC3-RFP-LC3dG) construct. (Addgene plasmid #84572; http://n2t.net/addgene:84572; RRID:Addgene 84572).

Funding

The authors disclose receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the U.S. National Institutes of Health (NIH) to J.N.S. (NINDS NS117968, NIA AG073734, and NIGMS GM131814).

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Authors and Affiliations

  1. Dept. of Biomedical Engineering, University of Minnesota, Minneapolis, MN, 55455, USA

    Elly E. Liao, Mu Yang, Noah Nathan Kochen, Nagamani Vunnam, Anthony R. Braun & Jonathan N. Sachs

  2. Dept. of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA

    David M. Ferguson

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  1. Elly E. Liao
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Contributions

E.E.L directed the study, designed, and performed cellular experiments, and wrote the manuscript; MY synthesized the compounds and edited the manuscript; NNK performed the DLS experiments; NV assisted with DLS and experiments probing the inflammatory signaling pathway; ARB conducted FLPR experiments and edited the manuscript; DMF edited the manuscript; and J.N.S. conceived of the study and edited the manuscript.

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Correspondence to Anthony R. Braun or Jonathan N. Sachs.

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Liao, E.E., Yang, M., Nathan Kochen, N. et al. Proteasomal Stimulation by MK886 and Its Derivatives Can Rescue Tau-Induced Neurite Pathology. Mol Neurobiol 60, 6133–6144 (2023). https://doi.org/10.1007/s12035-023-03417-5

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