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Cytoplasm, nucleus and endoplasmic reticulum differ in their responses towards toxic protein aggregation

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Amyloid-like protein aggregation is associated with neurodegeneration and many other pathologies. The nature of the toxic aggregate species and their mechanism of action remain elusive. We investigated how the quality control systems of different cellular compartments handle aggregation-prone proteins, by utilizing beta-sheet proteins that were designed de novo to form amyloid-like fibrils. Of the three compartments tested, aggregation in the cytoplasm was most toxic, and cytoplasmic aggregates interfered with nucleo-cytoplasmic protein and RNA transport. In contrast, the same proteins did not exhibit overt toxicity when forming inclusions in the nucleus. 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. Targeting the beta-proteins to the ER also resulted in a strong reduction of toxicity. The aggregation-prone proteins were retained within the ER in a soluble polymeric state, despite reaching very high concentrations exceeding those of ER-resident molecular chaperones. Our findings demonstrate a remarkable capacity of the ER and the nucleus to prevent the formation of toxic aggregates. However the two compartments use very different strategies to reduce the load of toxic aggregates and prevent harmful interactions.

This talk is part of the Biophysical Seminars series.

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