AUTHOR=Chen Li , Chen Guojie , Zhang Mengting , Zhang Xiaojie 

TITLE=Modeling sporadic juvenile ALS in iPSC-derived motor neurons explores the pathogenesis of FUSR503fs mutation

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 18 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2024.1364164

DOI=10.3389/fncel.2024.1364164

ISSN=1662-5102

ABSTRACT=Fused in sarcoma (FUS) mutations represent the most common genetic etiology of juvenile amyotrophic lateral sclerosis (JALS), for which effective treatments are lacking. In a prior report, we identified a novel FUS mutation, c.1509dupA: p.R503fs (FUS R503fs ), in a sporadic JALS patient. Structural analysis and predictions regarding physical and chemical properties of this mutation suggest that the reduction of phosphorylation and glycosylation sites, along with alterations in the amino acid sequence, may contribute to abnormal FUS accumulation within the cytoplasm and nucleus of induced pluripotent stem cell-derived motor neurons (MNs). Multielectrode array and calcium activity imaging indicate diminished spontaneous electrical and calcium activity signals in MNs harboring the FUS R503fs mutation. Transcriptomic analysis reveals upregulation of genes associated with viral infection and downregulation of genes involved in neural function maintenance, such as the ATP6V1C2 gene. Treatment with ropinirole marginally mitigates the electrophysiological decline in FUS R503fs MNs, suggesting the utility of this cell model for mechanistic exploration and drug screening.