Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS

Abstract

Amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration, paralysis, and death. Accurate disease modeling, identifyingdisease mechanisms, and developing therapeutics is urgentlyneeded. We previously reported motor neuron toxicity throughpostmortem ALS spinal cord-derived astrocytes. However, thesecells can only be harvested after death, and their expansion is limited.We now report a rapid, highly reproducible method to convertadult human fibroblasts from living ALS patients to induced neu-ronal progenitor cells and subsequent differentiation into astrocytes(i-astrocytes). Non-cell autonomous toxicity to motor neurons isfound following coculture of i-astrocytes from familial ALS patientswith mutation in superoxide dismutase or hexanucleotide expansion in C9orf72 (ORF 72 on chromosome 9) the two most frequentcauses of ALS. Remarkably, i-astrocytes from sporadic ALS patientsare as toxic as those with causative mutations, suggesting a commonmechanism. Easy production and expansion of i-astrocytes nowenables rapid disease modeling and high-throughput drug screeningto alleviate astrocyte-derived toxicity.