Dynamic molecular network analysis of iPSC differentiation to Purkinje cells delineates the role of ISG15 in temporal regulation of SCA1 pathology at the earliest stage

The earliest molecular pathology comes to focus in all the neurodegenerative diseases for expecting the extent of human therapeutics. We ask this question in spinocerebellar ataxia type 1 (SCA1), a rare familial neurodegenerative disease that primarily induces cell death and dysfunction of cerebellum Purkinje cells. Extensive prior studies have identified involvement of transcription or RNA-splicing factors in the molecular pathology of SCA1. However, the regulatory network of SCA1 pathology, especially central regulators of the earliest developmental stages and inflammatory events, remains incompletely understood. Here we elucidate the earliest developmental pathology of SCA1 using newly developed dynamic molecular network analyses of sequentially acquired RNA-seq data during differentiation of SCA1 patient-derived induced pluripotent stem cells (iPSCs) to Purkinje cells. The result of dynamic molecular network analysis uncovers the role of ISG15 to inhibit proteasome degradation of mutant ataxin-1 (Atxn1) and enhance disease protein accumulation in Purkinje cells of SCA1 model mice and human patients, to which molecular networks progressing from early embryonic stage finally reach after birth.