. Targeting protein homeostasis in sporadic inclusion body myositis. Sci Transl Med. 2016 Mar 23;8(331):331ra41. PubMed.


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  1. It is clear that there is a correlation between persistent higher order assembly of RNA-binding proteins and disease (including ALS, FTD and IBM). The most prominent protein is TDP-43, but similar behavior is observed for FUS, hnRNPA1, hnRNPA2B1, TIA-1, and hnRNPDL, and likely others. A normal feature of all of these RNA-binding proteins is assembly into dynamic structures to form ribonucleoprotein bodies (e.g., RNA granules) but these structures become less dynamic—more persistently assembled—in disease states. The assembly and disassembly of these structures is normally subject to several types of regulationchaperones contribute importantly to this (we showed this for DNAJB6 in a paper published last monthsee Li et al., 2016). I think the point of overlap between Chen et al. and Ahmed et al. is the idea that the chaperone system can be amplified to reverse abnormally persistent higher order assemblies of RNA-binding proteins, and that this is accompanied by therapeutic benefit.


    . Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy. Hum Mol Genet. 2016 Mar 1;25(5):936-50. Epub 2016 Jan 6 PubMed.

    View all comments by J. Paul Taylor
  2. DNAJ-Yeah!

    Hsp70 co-chaperones of the Hsp40 (DNAJ) family prevent formation of toxic aggregates

    Protein aggregates hallmark nearly all age-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), several polyglutamine (PolyQ) disorders such as Huntington’s disease (HD) and different forms of spinocerebellar ataxias (SCA1,2,3,6,7), as well as amyotrophic lateral sclerosis (ALS). This has been taken as evidence to suggest that a collapse in cellular protein homeostasis might be a central theme underlying these diseases and that boosting rate-limiting components of the cellular protein quality-control system might be a potential strategy to counteract protein aggregates or their toxic consequences (Balch et al., 2008). 

    In a recent paper in Brain from the groups of Christopher Shaw and Michael Cheetham, this paradigm was investigated for the Tar DNA binding protein 43 (TDP-43) that is a major constituent of aggregates that hallmark ALS and for which multiple mutations have been shown to be causative for heritable forms of the disease. Hereto, they first modulated a central regulator of the cellular protein quality-control system, heat shock transcription factor-1 (HSF-1). This transcription factor, amongst others, can elevate the expression of a set of proteins called heat shock proteins (HSPs) that play a central role in regulating protein quality control (Akerfelt et al., 2010). By binding to protein substrates, HSPs assist in both protein folding and protein degradation. In line with their expectations, HSF-1 activation was found to reduce, and HSF-1 inactivation to enhance, TDP-43 aggregation in several cell models, including rat primary cortical neurons.

    Since HSF-1 activates a broad spectrum of different HSPs at the same time, they next tested whether the upregulation of a single member of HSPs would suffice to suppress TDP-43 aggregation. Surprisingly, upregulation of several main targets of HSF-1 like Hsp70 (HSPA1A), Hsc70 (HSPA8), Hsp40 (DNAJB1) or Hsp27 (HSPB1) did not lead to a suppression of TDP-43 aggregation. However, the sole upregulation of a few members of the DNAJ (Hsp40-like) family of proteins, including DNAJB2a, DNAJB4, DNAJB6a, DNAJB6b, and DNAJB8, were as effective as activating HSF-1 in suppressing TDP-43.

    DNAJ proteins are considered to be co-chaperones of HSP70 machines: They are thought to bind protein substrates and “deliver” them for further client processing (Kampinga and Craig, 2010). For DNAJB2a, which the authors chose to further investigate, it was shown that the ability to interact with Hsp70 was crucial for DNAJB2a-mediated suppression of TDP-43 aggregation. However, a specific C-terminal domain of DNAJB2a that contains two ubiquitin interacting motifs (UIMs) that distinguish it from most other DNAJ family members, was found to be dispensable for aggregation suppression. These UIMs in DNAJB2a previously had been shown to be important for proteasomal targeting of substrates, such as mutants of superoxide dismutase-1 (SOD-1), which also cause ALS (Novoselov et al., 2013). In turn, the authors showed that DNAJB2a-mediated prevention of TDP-43 aggregation was unaffected by proteasomal inhibition. In addition, the fact that other co-chaperones, such asDNAJB4, DNAJB6a, DNAJB6b, and DNAJB8 (which lack such UIMs), were effective in suppressing TDP43 aggregation suggests that mechanisms other than promoting ubiquitin-directed protein degradation must be responsible for regulating TDP43 protein homeostasis.  The authors speculate that DNAJB2a might assist in TDP43 folding.

    Irrespective of what the mechanism might be, the data suggest again that DNAJ proteins could be excellent targets for combatting neurodegenerative protein aggregation diseases. Besides inhibiting aggregation of TDP43 and mutant SOD-1 (both causing ALS), DNAJ proteins have been shown to suppress aggregation and toxicity in models of PolyQ diseases. Strikingly, also for PolyQ diseases DNAJB2a, DNAJB6a, DNAJB6b, and DNAJB8 were amongst the most effective ones (Hageman et al., 2010). These proteins are closely related, evolutionarily, but yet have distinct structural features. What the communalities are that make them so effective in several of these aggregation diseases remains to be established. 

    How one may manipulate the levels or activity of these DNAJBs for therapeutic approaches remains unclear. Whilst HSF-1 activators have been developed, their potential for chronic treatment may be limited because along with having multiple targets they may come with unwanted side effects, and because activation of HSF-1 declines with age (Akerfelt et al., 2010). Moreover, it cannot yet be concluded from the work by Shaw et al. whether the HSF-1-mediated protection can really be attributed to DNAJB2a, as this would require HSF-1-activation experiments under conditions of blocking DNAJB2a induction. In fact, HSF-1 mediated protection could depend on mechanisms that are still distinct from direct DNAJB2b protection. Fortunately, however, all the DNAJB proteins identified as TDP43 suppressors are only weakly HSF-1-regulated, so options for their upregulation independent of HSF-1 activation might be found.


    . Adapting proteostasis for disease intervention. Science. 2008 Feb 15;319(5865):916-9. PubMed.

    . Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol. 2010 Aug;11(8):545-55. Epub 2010 Jul 14 PubMed.

    . The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol. 2010 Aug;11(8):579-92. PubMed.

    . Molecular chaperone mediated late-stage neuroprotection in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. PLoS One. 2013;8(8):e73944. Epub 2013 Aug 30 PubMed.

    . A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation. Mol Cell. 2010 Feb 12;37(3):355-69. PubMed.

    View all comments by Harm Kampinga

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