Abstract
The expression, misfolding, and aggregation of long repetitive amino acid tracts are a major contributing factor in a number of neurodegenerative diseases, including C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia, fragile X tremor ataxia syndrome, myotonic dystrophy type 1, spinocerebellar ataxia type 8, and the nine polyglutamine diseases. Protein aggregation is a hallmark of each of these diseases. In model organisms, including yeast, worms, flies, mice, rats, and human cells, expression of proteins with the long repetitive amino acid tracts associated with these diseases recapitulates the protein aggregation that occurs in human disease. Here we show that the model organism Dictyostelium discoideum has evolved to normally encode long polyglutamine tracts and express these proteins in a soluble form. We also show that Dictyostelium has the capacity to suppress aggregation of a polyglutamine-expanded Huntingtin construct that aggregates in other model organisms tested. Together, these data identify Dictyostelium as a novel model organism with the capacity to suppress aggregation of proteins with long polyglutamine tracts.
Highlights
The Dictyostelium proteome is predicted to encode a vast amount of homopolymeric amino acid tracts, including long polyglutamine tracts
We show that Dictyostelium has the capacity to suppress aggregation of a polyglutamine-expanded Huntingtin construct that aggregates in other model organisms tested
The uncharacterized cyclin domain-containing protein encoded by gene DDB_G0302543 contains an uninterrupted tract of 79 glutamines. To determine whether this and other polyglutamine proteins are expressed in Dictyostelium, we utilized the 1C2 antibody (␣-polyQ) that preferentially recognizes long polyglutamine tracts [22]
Summary
The Dictyostelium proteome is predicted to encode a vast amount of homopolymeric amino acid tracts, including long polyglutamine tracts. In model organisms, including yeast, worms, flies, mice, rats, and human cells, expression of proteins with the long repetitive amino acid tracts associated with these diseases recapitulates the protein aggregation that occurs in human disease. We show that the model organism Dictyostelium discoideum has evolved to normally encode long polyglutamine tracts and express these proteins in a soluble form. Polyglutamine expansion is thought to confer toxicity in a number of ways: altered folding, impaired degradation, abnormal interaction with other proteins, altered subcellular localization, and. 1 protein remains soluble in Dictyostelium, whereas it readily aggregates in yeast and mammalian cells Together, these data identify Dictyostelium as an organism with an unusual capacity to resist aggregation of proteins with long polyglutamine tracts
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