Editors' ChoiceGenetics

Modifying Genetic Disease

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Science Translational Medicine  03 Jul 2013:
Vol. 5, Issue 192, pp. 192ec109
DOI: 10.1126/scitranslmed.3006878

We are all genetic time bombs on the brink of disaster. The 1000 Genomes Project (www.1000genomes.org) revealed that the average healthy person harbors ~400 damaging mutations and ~2 bona fide disease-causing mutations in their genome; yet, we remain, for the most part, healthy. For this reason, instead of on disease genes more focus should be placed on modifier genes and protective alleles that prevent the genetic bomb from going off. Drugs that target those modifier gene pathways can then be developed. In this vein, Park et al. searched for modifiers of ataxin 1 (ATXN1) to treat spinocerebellar ataxia type 1 (SCA1)—a rare and fatal disease.

SCA1 is a neurodegenerative disease affecting the cerebellum and spinal cord that is caused by polyglutamine expansions in the gene encoding ATXN1. Reducing levels of ATXN1 protein can reverse the disease in animal models. Park et al. therefore screened for genetic modifiers of ATXN1 levels in human cell lines and in flies (Drosophila). By intersecting the results from the two screens, they were able to identify 10 highly conserved modifier genes that reduced ATXN1 levels and suppressed an eye-degeneration phenotype in flies expressing a mutant form of ATXN-1. The most enriched pathway among the modifier genes was the RAS/mitogen-activated protein kinase (MAPK) pathway. As such, the authors devised genetic strategies to inhibit components of the RAS/MAPK signaling pathway in a Drosophila SCA1 model carrying a mutant version of atxn1. Reduction of these modifier genes lowered the levels of ATXN1, prevented eye degeneration, and improved motor behavior in the flies. In human cells, pharmacological inhibition of MAPK signaling components reduced ATXN1 levels. They further found that MSK1 (mitogen- and stress-activated protein kinase) regulates ATXN1 levels by phosphorylating and stabilizing the protein. Genetically reducing MSK1 levels in a mouse model of SCA1 partially rescued neurodegenerative processes and improved motor performance.

This effort demonstrates the importance of studying modifier genes to develop new treatment strategies for seemingly intractable genetic diseases. The study also highlights the power of intersecting approaches from different model organisms in this effort. The next step will be to evaluate the efficacy of the available drugs that inhibit the RAS/MAPK pathway in mouse models and in patients, in order to translate these findings for SCA1 treatment.

J. Park et al., RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 498, 325–331 (2013). [Pub Med]

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