title: Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA.
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.
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Woerner
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Frottin
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hornburg
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
authors.forename: Li R
authors.initials: LR
authors.lastname: Feng
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Meissner
authors.affiliation: Neurobiochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Schillerstr. 44, D-80336 Munich, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Patra
authors.affiliation: 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.
authors.forename: Jörg
authors.initials: J
authors.lastname: Tatzelt
authors.affiliation: 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.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: 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.
authors.forename: Konstanze F
authors.initials: KF
authors.lastname: Winklhofer
authors.affiliation: 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.
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Hartl
authors.affiliation: 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.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hipp
mesh_terms: D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D066329:Protein Aggregates; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D066329:Protein Aggregates; D012333:RNA, Messenger