The Good and the Bad in ALS

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Science  21 Sep 2012:
Vol. 337, Issue 6101, pp. 1434
DOI: 10.1126/science.337.6101.1434-c

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron death. Development of effective therapies will require an understanding of the molecular and cellular mechanisms that go awry in the disease—insights that often come from genetic approaches. Mutational analyses of rare hereditary forms of ALS have already implicated >12 culprit genes. Although several of these genes converge on common pathways, the overall view of pathogenesis remains incomplete.

Recent studies have uncovered two new genetic mutations that have an impact on ALS; interestingly, in one case the mutations appear to have a salutary effect on the course of the disease. Through exome sequencing of two large ALS families, Wu et al. discovered disease-associated mutations in the PFN1 gene, which encodes the actin-binding protein profilin-1. In cultured cells, mutant profilin-1 formed insoluble aggregates and inhibited axonal outgrowth. Starting with a zebrafish model of ALS, Van Hoecke et al. discovered a disease-modifying gene called EPHA4, which encodes a receptor tyrosine kinase that interacts with ephrins, proteins involved in axonal repulsion. Inhibition of EphA4 signaling had beneficial effects in fish and rodent models of ALS. Importantly, two ALS patients who carried inactivating mutations in EPHA4 showed uncharacteristically long survival.

Nature 488, 499 (2012); Nat. Med. 18, 1418 (2012).

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