Screening of a kinase library in human Huntington disease iPSC derived striatal precursor neurons reveals a neuroprotective effect of PKC alpha and PKC beta1 inhibition

Jiang, M.; Shi, T.; Miryala, R.; Rodriguez, M.; Wang, R.; Sultania, R.; Guttman, L.; Johnston, J.; Li, Y.; Cui, A.; Belkas, K.; Xue, Y.; Um, Y.; Yuan, A.; Holland, C.; Troncoso, J. C.; Duan, W.; Ratovitski, T.; Smith, W.; Ross, C. A.

doi:10.1101/2025.09.18.677178

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bioRxiv · 10.1101/2025.09.18.677178

Screening of a kinase library in human Huntington disease iPSC derived striatal precursor neurons reveals a neuroprotective effect of PKC alpha and PKC beta1 inhibition

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Abstract

The loss of striatal medium spiny neurons is a hallmark of Huntingtons disease (HD). To identify potential disease-modifying treatments, we previously developed a human neuronal model by immortalizing and differentiating HD patient-derived iPSCs into highly homogeneous striatal precursor neurons (ISPNs). Using a 96-well screening platform, and two rounds of re-screening, we tested a kinase inhibitor library and identified 5 compounds that protected HD ISPNs from mutant huntingtin (mHTT)-induced toxicity. Among these, we prioritized the PKC-/{beta}1 inhibitor GO6976, which rescued HD ISPNs from mHTT toxicity in a dose-dependent manner. Further, we found increased phosphorylation of PKC- and PKC-{beta}1 in HD cells and tissues, while their overexpression was toxic to HD ISPNs. Knockdown of PKC-/{beta}1 protected the neurons, and both isoforms interacted and colocalized with HTT. These results suggest that PKC-/{beta}1 plays a role in HD neurodegeneration, and that inhibiting their activity may offer a potential therapeutic approach for HD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/677178v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@256d6org.highwire.dtl.DTLVardef@1931e7borg.highwire.dtl.DTLVardef@1b6598borg.highwire.dtl.DTLVardef@b0bbb5_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHD patient-derived iPSC-based striatal precursor neurons (ISPNs) were used to screen and identify neuroprotective compounds. C_LIO_LIThe PKC-/{beta}1 inhibitor GO6976 rescues HD ISPNs from mutant huntingtin (HTT)-induced toxicity. C_LIO_LIThe phosphorylation of PKC-/{beta}1 is elevated in HD cell and tissues, and PKC-/{beta}1 interact with both wild-type and mutant huntingtin. C_LIO_LIOverexpression of PKC-/{beta}1 is toxic to HD ISPNs, while its knockdown protects the neurons. C_LI

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Jiang, M., Shi, T., Miryala, R., Rodriguez, M., Wang, R., Sultania, R., Guttman, L., Johnston, J., Li, Y., Cui, A., Belkas, K., Xue, Y., Um, Y., Yuan, A., Holland, C., Troncoso, J. C., Duan, W., Ratovitski, T., Smith, W., Ross, C. A.. 2025-09-19. Screening of a kinase library in human Huntington disease iPSC derived striatal precursor neurons reveals a neuroprotective effect of PKC alpha and PKC beta1 inhibition. https://doi.org/10.1101/2025.09.18.677178

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