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Cytoplasmic protein aggregates interfere with nucleo-cytoplasmic transport of protein and RNA

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Science  03 Dec 2015:
aad2033
DOI: 10.1126/science.aad2033

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Abstract

Amyloid-like protein aggregation is associated with neurodegeneration and other pathologies. The nature of the toxic aggregate species and their mechanism of action remain elusive. Here we analyzed the compartment-specificity of aggregate toxicity using artificial β-sheet proteins as well as fragments of mutant huntingtin and TDP-43. Aggregation in the cytoplasm interfered with nucleo-cytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, impairment of nucleo-cytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases.

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