Patient-derived induced pluripotent stem cells (iPSCs) can be used as models for genetic diseases, as they can self-renew, be induced to differentiate and be used for drug screening. Now, Haruhisa Inoue and colleagues report the generation of motor neurons derived from iPSCs of individuals with amyotrophic lateral sclerosis (ALS) and describe their use in drug screening (Sci. Transl. Med. 4, 145ra104, 2012). The authors generated iPSCs from the dermal fibroblasts of three patients with ALS who had different heterozygous missense mutations affecting TDP-43 and used these cells to generate motor neurons. Characterization of the motor neurons showed that they recapitulate cellular phenotypes previously associated with ALS, including shorter neurites and decreased expression of neurofilaments relative to normal neurons. Expression profiling showed perturbations in RNA metabolism. The authors also found evidence of cytoplasmic aggregates of TDP-43. The authors screened four drugs known to modulate transcription through alteration to histone modification or RNA splicing: trichostatin A, spliceostatin A, anacardic acid and garcinol. They found that anacardic acid, a histone acetyltransferase inhibitor, protected against arsenite-induced motor neuron death, reduced the cytoplasmic mislocalization of TDP-43 and increased the length of neurites. This work provides proof of principle for the use of iPSCs to model a late-onset genetic disease.
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