Abstract
Huntington’s disease develops when the polyglutamine (polyQ) repeat in the Huntingtin (Htt) protein is expanded to over 35 glutamines rendering it aggregation-prone. Here, using Htt exon-1 as a polyQ model protein in a genome-wide screen in yeast, we show that the normal and soluble Htt exon-1 is toxic in cells with defects in type-1 myosin-dependent endocytosis. The toxicity of Htt is linked to physical interactions with type-1 myosins, which occur via the Htt proline-rich region, leading to a reduction in actin patch polarization and clathrin-dependent endocytosis. An expansion of the polyQ stretch from 25 to 103 glutamines, which causes Htt aggregation, alleviated Htt toxicity in cells lacking Myo5 or other components involved in early endocytosis. The data suggest that the proline-rich stretch of Htt interacts with type-1 myosin/clathrin-dependent processes and demonstrate that a reduction in the activity of such processes may result in a positive selection for polyQ expansions.
Highlights
Huntington’s disease (HD) is one of several neurological diseases caused by polyQ expansions in specific proteins
The aggregation pattern of Htt exon-1 mimics that of mammalian cells; the protein with a glutamine stretch of 25 repeats is soluble in the cytoplasm, while repeat lengths of 47 or more lead to protein aggregation and the formation of typical IBs5
Such inclusion bodies (IBs) of exon-1 were suggested to be the cause of HD, but recent studies have suggested that smaller exon-1 oligomers/aggregates are the toxic conformers[6,7,8]
Summary
Huntington’s disease (HD) is one of several neurological diseases caused by polyQ expansions in specific proteins. (c) Native PAGE of protein extracts from wild type and myo5Δ cells expressing HTT constructs.
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