What is it about?

Several human proteins that form amyloid-like aggregates in patients with neurodegenerative diseases also are toxic and form aggregates in model organisms including yeast and flies, making them good disease models. Since mutations in the calcium-responsive transactivator (CREST) chromatin-remodeling protein, are associated with ALS, we set out to make a CREST model system of ALS in yeast. Here we show that CREST is toxic in yeast and flies and forms nuclear and occasionally cytoplasmic foci that stain with Thioflavin-T, a dye indicative of an amyloid-like protein. We also show in yeast that the HSP104 chaperone required for propagation of yeast prions is likewise required for CREST toxicity. Furthermore, deletion of HSP104 affects CREST aggregation. ATXN2, previously shown to modify ALS toxicity caused by mutations in the TDP-43 encoding gene, also modifies toxicity of CREST expressed in either yeast or flies.

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Why is it important?

These results provide a new yeast and fly model for ALS. The results also show that ATXN2 alters the toxicity of another ALS-associated protein besides TDP-43, namely CREST. This gives hope that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.


Studying candidate therapeutic drugs in either the yeast or fly model established here is much easier than testing drugs in a mammal. I hope these models will be used to lead to effective drugs.

Susan Liebman
University of Nevada Reno

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This page is a summary of: Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies, PLoS Genetics, August 2019, PLOS, DOI: 10.1371/journal.pgen.1008308.
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