Mutations in the protein kinase C gamma (PKC gamma) gene cause spinocerebellar ataxia type 14 (SCA14), a heterogeneous neurodegenerative disorder. Synthetic peptides (C1 B1) serve as gap junction inhibitors through activation of PKC gamma control of gap junctions. We investigated the neuroprotective potential of these peptides against SCA14 mutation-induced cell death using neuronal HT22 cells. The C1B1 synthetic peptides completely restored PKC gamma enzyme activity and subsequent control of gap junctions. PKC gamma SCA14 mutant proteins were shown to cause aggregation which initially resulted in endoplasmic reticulum (ER) stress and cell apoptosis as demonstrated by phosphorylation of PERK on Thr981, activation of caspase-12, increases in BiP/GRP78 protein levels, and consequent activation of caspase-3. Pre-incubation with C1B1 peptides completely abolished these SCA14 effects on ER stress and caspase-3 activation, suggesting that C1B1 peptides protect cells from apoptosis through inhibition of gap junctions by restoration of PKC gamma control of gap junctions, which may result in neuroprotection in SCA14. (C) 2007 Elsevier Inc. All rights reserved.