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. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013 Mar 28;495(7442):467-73. PubMed.


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  1. This study by Paul Taylor and Jim Shorter is highly interesting to my laboratory. We study how RNA-binding proteins (RBPs) affect RNA processing in the context of neurobiology and neurodegenerative diseases. This study shows that prion-like domains or "low-complexity sequences" (Kato et al., 2012) seem to play a key role in RNA granule assembly, in particular, during cellular stress. The observation that these glycine-rich domains are found within these heterogeneous nuclear ribonucleoproteins (hnRNPs) A2/B1 and A1 (as well as TDP-43 and FUS/TLS), and that defects in these regions result in aberrant/enhanced polymerization and recruitment into stress granules, underscores the importance of understanding the normal function of these RBPs during stress. HnRNP proteins are involved with controlling alternative splicing, RNA stability, and polyadenylation of endogenous substrates in a variety of cell types.

    Paul and Jim's fascinating study leads to several key questions. First, why are these proteins implicated in RNA granule assembly/formation? Second, does a disruption in RNA granule recruitment cause a disruption of RNA metabolism? Third, we showed that more than half of alternative exons regulated by hnRNP proteins are affected by more than two hnRNPs (Huelga et al., 2012), implying synergistic actions by these hnRNPs on mRNA targets. Are other hnRNPs also implicated in neurological disease, given the large degree of crosstalk among hnRNP proteins? Last, is there cell-type specific vulnerability—and are RNA substrates that are affected during stress granule formation different in the brain, muscle, and bone?


    . Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell. 2012 May 11;149(4):753-67. PubMed.

    . Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins. Cell Rep. 2012 Feb 23;1(2):167-78. PubMed.

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  1. Disease Mutations Zip Lock Stress Granules in Proteinopathy, ALS