Abstract
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.
Highlights
Mutations in an increasing number of human genes have been found to cause familial neurodegenerative disease [1,2]
We show that the HSP104 chaperone required for propagation of yeast prions is likewise required for calcium-responsive transactivator (CREST) toxicity
We show that CREST toxicity is increased by the endogenous yeast [PIN+] prion and reduced by deletion of the HSP104 chaperone that is required for propagation of many yeast prions [4]
Summary
Mutations in an increasing number of human genes have been found to cause familial neurodegenerative disease [1,2] Proteins encoded by these genes are often soluble in healthy individuals, but form insoluble amyloid-like aggregates that seed further aggregation in the neurons of patients with disease. Such conformational changes have been seen for: Aβ, associated with Alzheimer’s disease; α-synuclein with Parkinson’s disease; TDP-43, FUS and others with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); and huntingtin with Huntington’s disease. The endogenous yeast prion [PIN+] (sometimes called [RNQ+]), which is an amyloid form of the RNQ1 protein, promotes the de novo aggregation of the SUP35 protein to form the [PSI+] prion. This could occur by cross-seeding or by sequestration of proteins such as chaperones by the amyloid [PIN+] prion [8,16,17,18,19,20,21,22,23,24,25,26,27]
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