Researchers Develop Drug-Screening Platform For Lou Gehrig’s Disease

Researchers in Japan have developed a new drug screening assay to study familial amyotrophic lateral sclerosis, a late-onset, fatal disorder which is also known as Lou Gehrig’s disease.

AsianScientist (Aug. 13, 2012) – Researchers in Japan have developed a new in vitro drug screening assay to study familial amyotrophic lateral sclerosis (ALS), a late-onset, fatal disorder which is also known as Lou Gehrig’s disease.

In a study published online in Science Translational Medicine, researchers at the Center for iPS Cell Research and Application (CiRA) at Japan’s Kyoto University recapitulated ALS-like defects in motor neurons differentiated from induced pluripotent stem cells (iPSCs).

The iPSCs were derived from three patients with familial ALS who have mutations in Tar DNA-binding protein-43 (TDP-43).

Associate Professor Haruhisa Inoue and his team showed that the ALS motor neurons had increased vulnerability to stress, shorter neurites, and cytosolic aggregates similar to those seen in postmortem tissues from ALS patients.

The team also unraveled the mechanism of ALS onset. They found that TDP-43 mRNA was upregulated in the ALS motor neurons, which means that TDP-43 autoregulation was disturbed, and that the detergent-insoluble form of TDP-43 aggregated with the splicing factor SNRPB2 in the nucleus, perturbing RNA metabolism.

Using the ALS motor neurons as a disease model for drug screening, the team further found that the chemical compound anacardic acid could rescue abnormal ALS phenotypes in vitro.

When anacardic acid, a histone acetyltransferase inhibitor, was added to the motor neurons, TDP-43 mRNA expression was decreased, and the length of the neurites increased.

“Our work represents an initial stage of drug screening for ALS using patient-specific iPSCs. TDP-43 is not only relevant to familial ALS but also to sporadic ALS, which represents the majority of ALS cases,” said Inoue, who is the senior author on the paper.

“We will continue to work on ALS patient-specific iPSCs in order to help develop new drug seeds and candidates,” he said.

The article can be found at: Egawa N et al. (2012) Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells.

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Source: CiRA.
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