期刊
SCIENCE
卷 351, 期 6269, 页码 173-176出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aad2033
关键词
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资金
- European Commission [FP7 GA ERC-2012-SyG_318987-ToPAG]
- Munich Cluster for Systems Neurology
- German Research Foundation
- Hans and Ilse Breuer Foundation
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 beta-sheet proteins, as well as fragments of mutant huntingtin and TAR DNA binding protein-43 (TDP-43). Aggregation in the cytoplasm interfered with nucleocytoplasmic 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 nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases.
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