Cells form RNA granules under stress to focus their energy on producing proteins needed for survival. These stress granules, which are assembled through a biophysical process known as a liquid-liquid phase transition, are membrane-less organelles that keep mRNAs out of cytoplasmic circulation by sequestering them, likely stalling their translation during the initiation phase (Buchan and Parker, 2009).
The assembly of stress granules, according to in vitro studies, is driven by low-complexity sequence domains (LCDs) of RNA-binding proteins (RNPs) including FUS and hnRNPA1 (see October 2015 news; Kato et al., 2012). But in ALS, these sequences can be disrupted, leading to biophysical changes in these granules which may contribute to the disease (Kim et al., 2013; Molliex et al. 2015; Murakami et al., 2015; Patel et al., 2015).
Now, a University of Pennsylvania team led by Erika Holzbaur report that ALS-linked mutations in the LCD of TDP-43 increase the viscosity of RNA granules and impair their mobility within cultured rat cortical axons (Gopal et al., 2017). The findings suggest that stress granules are fluid and dynamic. But in ALS, these granules become sticky and therefore, may aggregate, which may lead to RNA dysregulation, toxicity and neurodegenerative disease (Lagier-Tourenne et al., 2012; Murakami et al., 2015).
The study is the first to investigate the potential impact of ALS on the biophysical nature of RNA granules in neurons. The findings are published online on March 6 in the Proceedings of the National Academy of Sciences.
Researchers first suspected that stress granules may play a role in ALS by studying the role of ALS-linked RNA-binding proteins in the disease (Bosco et al., 2010, Dormann et al., 2010). However, in more recent years, researchers discovered that these RNA granules may play a more general role in ALS, including the most common form of the disease.
Arginine-rich dipeptide repeat proteins associated with C9orf72 ALS appear to drive the formation of stress granules – at least in vitro according to a study published this week in Molecular Cell (see March 2017 news). The study, led by University of Leuven’s Ludo van den Bosch in Belgium, adds to growing evidence that these dipeptide proteins may also contribute to the C9orf72-linked form of the disease (see March 2016 news; Khosravi et al., 2016; Zhang et al., 2016).
The report comes at the heels of a 2014 study from the laboratory of Aaron Gitler at Stanford University in California that found that ALS-linked mutations in profilin 1 led to defects in RNA stress granule dynamics (Figley et al., 2014).
Together, the results suggest that changes in the biophysical nature of stress granules may be a general mechanism of ALS. And, targeting the assembly of these stress granules may be helpful in tackling the disease.
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