RT Journal Article
SR Electronic
T1 Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 415927
DO 10.1101/415927
A1 By Sangeun Park
A1 Sei-Kyoung Park
A1 Naruaki Watanabe
A1 Tadafumi Hashimoto
A1 Takeshi Iwatsubo
A1 Tatyana A. Shelkovnikova
A1 Susan W. Liebman
YR 2019
UL http://biorxiv.org/content/early/2019/06/18/415927.abstract
AB Proteins associated with familial neurodegenerative disease often aggregate in patients’ neurons. Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Deletion of the ATXN2 ortholog, PBP1, reduces yeast TDP-43 toxicity, which led to identification of ATXN2 as an amyotrophic lateral sclerosis (ALS) risk factor and therapeutic target. Likewise, new yeast neurodegenerative disease models could facilitate identification of other risk factors and targets. Mutations in SS18L1, encoding the calcium-responsive transactivator (CREST) chromatin-remodeling protein, are associated with ALS. We show that CREST is toxic in yeast and forms nuclear and occasionally cytoplasmic foci that stain with Thioflavin-T, a dye indicative of amyloid-like protein. Like the yeast chromatin-remodeling factor SWI1, CREST inhibits silencing of FLO genes. Toxicity of CREST is enhanced by the [PIN+] prion and reduced by deletion of the HSP104 chaperone required for the propagation of many yeast prions. Likewise, deletion of PBP1 reduced CREST toxicity and aggregation. In accord with the yeast data, we show that the Drosophila ortholog of human ATXN2, dAtx2, is a potent enhancer of CREST toxicity. Downregulation of dAtx2 in flies overexpressing CREST in retinal ganglion cells was sufficient to largely rescue the severe degenerative phenotype induced by human CREST. Overexpression caused considerable co-localization of CREST and PBP1/ATXN2 in cytoplasmic foci in both yeast and mammalian cells. Thus, co-aggregation of CREST and PBP1/ATXN2 may serve as one of the mechanisms of PBP1/ATXN2-mediated toxicity. These results extend the spectrum of ALS associated proteins whose toxicity is regulated by PBP1/ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.Author summary Mutations in the calcium-responsive transactivator (CREST) protein have been shown to cause amyotrophic lateral sclerosis (ALS). Here we show that the human CREST protein expressed in yeast forms largely nuclear aggregates and is toxic. We also show 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. In addition, deletion of the yeast ATXN2 ortholog reduces CREST aggregation. These results extend the spectrum of ALS associated proteins whose toxicity is regulated by ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.