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

The loss of striatal medium spiny neurons is a hallmark of Huntington's 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-α/β1 inhibitor GO6976, which rescued HD ISPNs from mHTT toxicity in a dose-dependent manner. Further, we found increased phosphorylation of PKC-α and PKC-β1 in HD cells and tissues, while their overexpression was toxic to HD ISPNs. Knockdown of PKC-α/β1 protected the neurons, and both isoforms interacted and colocalized with HTT. These results suggest that PKC-α/β1 plays a role in HD neurodegeneration, and that inhibiting their activity may offer a potential therapeutic approach for HD.