Skip to main content

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

Citations of this article
Mendeley users who have this article in their library.
Get full text


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.




Chung, Y. H., Lin, C. W., Huang, H. Y., Chen, S. L., Huang, H. J., Sun, Y. C., … Hsieh-Li, H. M. (2020). Targeting Inflammation, PHA-767491 Shows a Broad Spectrum in Protein Aggregation Diseases. Journal of Molecular Neuroscience, 70(7), 1140–1152.

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free