Neuroprotective modulation of the unfolded protein response in Marinesco-Sj?gren syndrome: PERK signaling inhibition and beyond

Individuals with Marinesco-Sj?gren syndrome(MSS;OMIM 248800),a genetic disease of infancy,suffer various disabilities,including loss of motor coordination due to cerebellar degeneration,and skeletal muscle weakness.After a progressive phase,symptoms stabilize and patients live to old age.Therefore,any pharmacological treatment that delays or attenuates cerebellar degeneration and/or muscle pathology can significantly improve their quality of life.We recently found that inhibiting the protein kinase RNA-like endoplasmic reticulum

Individuals with Marinesco-Sjogren syndrome （MSS; OMIM 248800）, a genetic disease of infancy, suffer var- ious disabilities, including loss of motor coordination due to cerebellar degeneration, and skeletal muscle weak- ness. After a progressive phase, symptoms stabilize and patients live to old age. Therefore, any pharmacological treatment that delays or attenuates cerebellar degenera- tion and/or muscle pathology can significantly improve their quality of life. We recently found that inhibiting the protein kinase RNA-like endoplasmic reticulum kinase （PERK） delays cerebellar degeneration, and ameliorates motor function and muscle pathology in a MSS mouse model （Grande et al., 2018）. This is the first preclinical study of a pharmacological treatment for MSS. Here we summarize our findings, and discuss how this therapeutic strategy might be improved for effective treatment.