A Stem Cell-Based Screening Platform Identifies Compounds that Desensitize Motor Neurons to Endoplasmic Reticulum Stress.

摘要: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease selectively targeting motor neurons in the brain and spinal cord. The reasons for differential neuron susceptibility remain elusive. We developed stem cell-based assay to study cell-autonomous mechanisms causing degeneration, with implications ALS. A small-molecule screen identified cyclopiazonic acid (CPA) as stressor which cell-derived were more sensitive than interneurons. CPA induced endoplasmic reticulum stress unfolded protein response. Furthermore, resulted an accelerated degeneration of expressing human superoxide dismutase 1 (hSOD1) carrying ALS-causing G93A mutation, compared wild-type hSOD1. secondary compounds that alleviated CPA-mediated degeneration: three kinase inhibitors tauroursodeoxycholic (TUDCA), bile derivative. neuroprotective effects these validated mutated SOD1 allele (hSOD1A4V). Moreover, we found administration TUDCA hSOD1G93A mouse model ALS reduced muscle denervation. Jointly, results provide insights into contributing preferential neurons, they demonstrate utility discovery new compounds.