. 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. What an interesting and fantastic story! The hnRNP A2B1 gene was the top candidate in our recent isolation of proteins binding to the C9ORF72 hexanucleotide repeats (Mori et al., 2013). Moreover, we also saw for another hnRNP (hnRNP A3) a cytoplasmic redistribution and nuclear clearance. That protein also contains the domain where the mutations were found in hnRNPA2B1 and hnRNPA1. Furthermore, we previously proposed that stress granules may be "precursors" of the final deposits (Dormann and Haass, 2011; Dormann et al., 2010). To convert reversible stress granules into insoluble deposits, we proposed additional stress was necessary, and one may speculate now that such stress may come from mutant hnRNPs, which could serve as seeds for irreversible aggregation and maybe even spreading. However, we could not confirm that mutations in TDP-43 favor stress granule formation (Bentmann et al., 2012). Nevertheless, the identification of disease-causing mutations in hnRNPA2B1 and hnRNPA1 unequivocally proves that at least these two hnRNPs are directly involved in the disease, and, based on the strong sequence homology, I would also predict that mutations will be found in hnRNPA3. Finally, these findings further support the important role of RNA binding proteins in ALS, FTLD, and related multisystem proteinopathies.


    . hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol. 2013 Mar;125(3):413-23. PubMed.

    . TDP-43 and FUS: a nuclear affair. Trends Neurosci. 2011 Jun 21; PubMed.

    . ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J. 2010 Aug 18;29(16):2841-57. PubMed.

    . Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43). J Biol Chem. 2012 Jun 29;287(27):23079-94. PubMed.

    View all comments by Christian Haass
  2. This collaborative research study provides new clues into how mutations in RNA-binding proteins may lead to degenerative disease. In the search for a causative gene mutation in a family with inherited multisystem proteinopathy (MSP) that was negative for VCP mutations, the authors identified a pathogenic mutation in the gene that codes for the heterogeneous nuclear ribonucleoprotein hnRNPA2B1. Intriguingly, genetic analysis of a second VCP-negative MSP family and an ALS family identified similar mutations in hnRNPA1. Given that the protein products of these genes function as “housekeepers” with critical roles in mRNA processing, these gene discoveries add to the growing body of evidence that dysfunctional mRNA metabolism plays a major role in degenerative disease.

    Muscle biopsies of affected individuals of the MSP families revealed abnormal sarcoplasmic inclusions of hnRNPA2B1, hnRNPA1, and TDP-43 in a subset of muscle fibers. This type of pathology is not completely unexpected, given that cytoplasmic inclusions of nuclear RNA binding proteins—especially TDP-43—in affected cells are a hallmark of ALS and related disorders. Kudos to the researchers who left no stone unturned and investigated the molecular triggers that drive this pathology by using computational algorithms. This bioinformatics-based analysis revealed that the disease-linked mutations fall into predicted prion-like domains of hnRNPA2B1 and A1, and strengthen a steric zipper motif, which accelerates self-seeding fibrillization. The implications of such increased propensity to form fibrils could be multifold. First, as shown in cell culture, it appears to increase the recruitment of hnRNPA2B1 and A1 into cytoplasmic stress granules, with likely negative consequences on RNA metabolism. Second, while not directly addressed in this study, it may also explain the regional cell-to-cell spreading pathology that is so typical for ALS and MSP. Whether this self-seeding fibrillization can be arrested is an important question for future research.

    View all comments by Amelie K. Gubitz
  3. 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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