Pharmacological rescue of motor neuron health by riluzole in patient-derived motor neurons

Heterogeneous and predominantly sporadic neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) remain highly challenging to model. Patient-derived induced pluripotent stem cell (iPSC) technologies offer great promise for these diseases, however large-scale studies demonstrating accelerated neurodegeneration from sporadic patients are limited. We generated an iPSC library from 100 sporadic ALS (SALS) patients and conducted population-wide phenotypic screening. SALS patient-derived motor neurons recapitulated key aspects of SALS, including reduced survival, accelerated neurite degeneration correlating with donor survival, transcriptional dysfunction, and pharmacological rescue by riluzole. Here we sought to determine if riluzole treatment reversed the disease process in patient-derived motor neurons by RNAseq profiling of riluzole treated vs untreated motor neurons from 9 ALS donors. Overall design: RNAseq profiling of patient-derived motor neurons from 9 ALS donors treated with DMSO or riluzole (2.5uM) from day 36 onwards. Samples collected at day neurite collapse reaches 50% of peak health in DMSO treated (LD50).