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Targeting Inflammation, PHA-767491 Shows a Broad Spectrum in Protein Aggregation Diseases

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Abstract

Many protein aggregation diseases (PAD) affect the nervous system. Deposits of aggregated disease-specific proteins are found within or around the neuronal cells of neurodegenerative diseases. Although the main protein component is disease-specific, oligomeric aggregates are presumed to be the key agents causing the neurotoxicity. Evidence has shown that protein aggregates cause a chronic inflammatory reaction in the brain, resulting in neurodegeneration. Therefore, strategies targeting anti-inflammation could be beneficial to the therapeutics of PAD. PHA-767491 was originally identified as an inhibitor of CDC7/CDK9 and was found to reduce TDP-43 phosphorylation and prevent neurodegeneration in TDP-43 transgenic animals. We recently identified PHA-767491 as a GSK-3β inhibitor. In this study, we established mouse hippocampal primary culture with tau-hyperphosphorylation through the activation of GSK-3β using Wortmannin and GF109203X. We found that PHA-767491 significantly improved the neurite outgrowth of hippocampal primary neurons against the neurotoxicity induced by GSK-3β. We further showed that PHA-767491 had neuroprotective ability in hippocampal primary culture under oligomeric Aβ treatment. In addition, PHA-767491 attenuated the neuroinflammation in mouse cerebellar slice culture with human TBP-109Q agitation. Further study of SCA17 transgenic mice carrying human TBP-109Q showed that PHA-767491 ameliorated the gait ataxia and the inflammatory response both centrally and peripherally. Our findings suggest that PHA-767491 has a broad spectrum of activity in the treatment of different PAD and that this activity could be based on the anti-inflammation mechanism.

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Abbreviations

AD:

Alzheimer’s disease

ANOVA:

analysis of variance

DIV:

days in vitro

DRPLA:

dentatorubral-pallidoluysian atrophy

FDA:

Food and Drug Administration

GFAP:

glial fibrillary acidic protein

GRAS:

generally recognized as safe

HD:

Huntington’s disease

LSD:

least significant difference

PD:

Parkinson’s disease

polyQ:

polyglutamine

SBMA:

spinal and bulbar muscular atrophy

SCA:

spinocerebellar ataxias

SCA17:

spinocerebellar ataxia type 17

TBP:

TATA box-binding protein

TBS:

tris-buffered saline

TG:

transgenic

WT:

wild-type

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Acknowledgments

Our gratitude is extended to the Molecular Imaging Core Facility of the National Taiwan Normal University under the auspices of the Ministry of Science and Technology.

Funding

This work was supported by research grants MOST 107-2320-B-003-007, 107-2320-B-003-009, and 104-2320-B-003-009-MY3 from the Ministry of Science and Technology.

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Author notes

  1. Yu-Han Chung and Chia-Wei Lin contributed equally to this work.

Authors and Affiliations

  1. Department of Life Science, National Taiwan Normal University, Taipei, Taiwan

    Yu-Han Chung, Chia-Wei Lin, Hsin-Yu Huang, Shu-Ling Chen, Guan-Chiun Lee, Guey-Jen Lee-Chen & Hsiu Mei Hsieh-Li

  2. Department of Nursing, Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan

    Hei-Jen Huang

  3. Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan

    Ying-Chieh Sun

  4. Department of Pharmacy, Taiwan Adventist Hospital, Taipei, Taiwan

    Ya-Ching Chang

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  1. Yu-Han Chung
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  4. Shu-Ling Chen
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  9. Ya-Ching Chang
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  10. Hsiu Mei Hsieh-Li
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Correspondence to Ya-Ching Chang or Hsiu Mei Hsieh-Li.

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All of the animal experiments were conducted according to the guidelines and were approved by the Research Committee of the National Taiwan Normal University (No. 103022).

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Chung, YH., Lin, CW., Huang, HY. et al. Targeting Inflammation, PHA-767491 Shows a Broad Spectrum in Protein Aggregation Diseases. J Mol Neurosci 70, 1140–1152 (2020). https://doi.org/10.1007/s12031-020-01521-y

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