Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA
Location, location, location Aggregates of certain disease associated proteins are involved in neurodegeneration. Woerner et al. now show that the exact location of these aggregates in the cell may be the key to their pathology (see the Perspective by Da Cruz and Cleveland) An artificial aggregate prone protein caused problems when expressed in the cytoplasm but not when expressed in the nucleus. Cytoplasmic aggregates interfered with nucleocytoplasmic import and export. Perhaps if we can shunt pathological aggregates to the nucleus in the future, we will be able to ameliorate some forms of degenerative disease. Science, this issue p. 173; see also p. 125 Protein aggregates in the cytoplasm soak up accessory factors needed for transport of other proteins and RNA across the nuclear envelope. [Also see Perspective by Da Cruz and Cleveland] 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 b 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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