. Potentiated Hsp104 variants suppress toxicity of diverse neurodegenerative disease-linked proteins. Dis Model Mech. 2014 Oct;7(10):1175-84. Epub 2014 Jul 25 PubMed.


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  1. This manuscript by Jackrel and Shorter is an extension of the tour de force Cell paper published by these authors earlier this year (Jackrel et al., 2014). In that manuscript, they engineered the protein disaggregase Hsp104,which normally has no activity against neurodegenerative disease associated amyloid aggregates, to possess a remarkable ability to attack diverse human disease protein aggregates, including α-synuclein, TDP-43, and FUS. These enhanced Hsp104 variants now open up the possibility for harnessing Hsp104’s protein disaggregase function as a therapeutic approach.

    This manuscript represents an important extension to the previous work because it makes three critical advances:

    It demonstrates that the enhanced Hsp104 variants also possess disaggregase activity against the disease-linked mutant versions of the disease proteins α-synuclein, TDP-43, FUS, and TAF15. Since these mutants enhance aggregation of the proteins, it was possible that Hsp104 would not be able to disaggregate them. But now the authors report that their enhanced-activity Hsp104 variants do indeed function robustly against these mutants.

    Secondly, they report that enhanced Hsp104 variants do not suppress aggregation or toxicity of EWSR1, a FUS-related protein linked to ALS and FTLD. This is intriguing given the similarity of EWSR1 and FUS. The finding indicates that these Hsp104 variants possess some substrate specificity. This point was not clear from the original manuscript.

    Lastly, the authors now provide in vitro studies to show mechanistically how Hsp104 recognizes substrates and how their enhanced variants do so differently. These findings are important because they represent a path forward to understanding how the variants might be harnessed to become more substrate-specific (e.g., to only work on certain disease proteins).


    . Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell. 2014 Jan 16;156(1-2):170-82. PubMed.

    View all comments by Aaron Gitler
  2. The new findings by Jackrel and Shorter are an important and exciting extension of their previous work published earlier this year. They had previously engineered a variant of Hsp104 to reverse aggregation of misfolded proteins associated with Parkinson's disease and ALS, including synuclein and RNA-binding protein TDP43. Their new findings show that the potentiated Hsp104 can, in fact, reverse aggregation of a broader array of disease proteins, including mutant forms of RNA-binding proteins. These findings show the broad utility of potentiated Hsp104. More importantly, they show that potentiated Hsp104 can correct the mislocalization of mutant TDP43 and FUS and retarget these proteins back to the nucleus where they belong. Mislocalization of these proteins has previously been shown by the Finkbeiner lab to be a tight predictor of their toxicity and, consistent with that, Jackrel and Shorter find that potentiated Hsp104 reduces toxicity of these proteins in yeast and worm models of disease. It will be exciting to see how potentiated Hsp104 behaves in other models of neurodegeneration, including iPS cell-derived neurons from patients who carry mutations in these genes and also sporadic ALS patients who do not carry these known mutations. Their engineered Hsp104 has great therapeutic potential for many neurodegenerative diseases, although many challenges still remain, including a mechanism for delivery.

    View all comments by Ashkan Javaherian

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