For example, we previously showed that halofuginone-dependent GCN2 activation restored cellular ER stress sensitivity and mitochondrial electron transport chain activity in cells deficient in the alternative ISR kinase PERK23 – a model of neurodegenerative diseases associated with reduced PERK activity such as PSP and AD.72,73 Compounds that activate other ISR kinases are similarly predicted to promote the direct remodeling of mitochondrial pathways to influence these and other functions. This evidence concerns the gene EIF2AK4 and neurodegenerative disease.