Format

Send to

Choose Destination
Science. 2016 Jan 8;351(6269):173-6. doi: 10.1126/science.aad2033. Epub 2015 Dec 3.

Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA.

Author information

1
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
2
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
3
Neurobiochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Schillerstr. 44, D-80336 Munich, Germany.
4
Neurobiochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Schillerstr. 44, D-80336 Munich, Germany. Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Universitätsstraße 150, D-44801 Bochum, Germany.
5
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany. Munich Cluster for Systems Neurology (SyNergy), D-80336 Munich, Germany.
6
Neurobiochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Schillerstr. 44, D-80336 Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), D-80336 Munich, Germany. Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Universitätsstraße 150, D-44801 Bochum, Germany.
7
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany. Munich Cluster for Systems Neurology (SyNergy), D-80336 Munich, Germany. hipp@biochem.mpg.de uhartl@biochem.mpg.de.

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 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.

PMID:
26634439
DOI:
10.1126/science.aad2033
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center