. Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21777-82. PubMed.

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  1. This important study establishes for the first time a genetic risk factor for sporadic ALS, thus providing a long-sought entry point into mechanisms and genetics of ALS. Genetic risk factors for neurodegenerative diseases will likely lead to novel insights into mechanisms of disease.

    The impact of the chromogranin B mutations is slightly lower than that of the ApoE4 allele in Alzheimer disease. Because the chromogranin B mutations had an impact on onset time in familial ALS, and on risk of disease in sporadic ALS, the findings provide important support for the notion that sporadic and familial ALS are mechanistically related.

    Chromogranin has been linked to mutant SOD1 by two previous studies. A frequently raised question is to what extent SOD1-based ALS mice are relevant in mimicking human disease. The association to chromogranin B in the SOD1 mouse model and now patient cohorts for both sporadic and familial ALS strongly supports the notion of converging cellular and molecular mechanisms of disease.

    One important implication for scientists working on ALS is that the research mechanistically links SOD1 mutations to a set of mutations in chromogranin B. We now have potentially interacting mutations in two genes to study; this will likely lead to new disease models and hopefully to first elements of a molecular disease pathway. It will be interesting to determine whether there is a relationship between mutant SOD1 secretion and chromogranin B mutations. Should this be the case, it may suggest that the risk involves local secretion of misfolded proteins such as mutant SOD1. Of further interest are the implications for the role of ER stress pathways in the pathogenesis of ALS.

    It will be important to determine whether other genes implicated in ALS (including the RNA metabolism genes TDP-43 and FUS) also synergize with chromogranin B mutations to promote disease. Whether chromogranin A variants link to ALS is definitely worth investigating as well.

    View all comments by Pico Caroni

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  1. Chromogranin B: The ApoE of ALS?