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| Home > Publications Database > Cytoplasmic poly-GA aggregates impair nuclear import of TDP-43 in C9orf72 ALS/FTLD. > print |
| 001 | 139127 | ||
| 005 | 20240321220547.0 | ||
| 024 | 7 | _ | |a 10.1093/hmg/ddw432 |2 doi |
| 024 | 7 | _ | |a pmid:28040728 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC5409121 |2 pmc |
| 024 | 7 | _ | |a 0964-6906 |2 ISSN |
| 024 | 7 | _ | |a 1460-2083 |2 ISSN |
| 024 | 7 | _ | |a altmetric:15289875 |2 altmetric |
| 037 | _ | _ | |a DZNE-2020-05449 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 570 |
| 100 | 1 | _ | |a Khosravi, Bahram |0 P:(DE-2719)2811528 |b 0 |e First author |u dzne |
| 245 | _ | _ | |a Cytoplasmic poly-GA aggregates impair nuclear import of TDP-43 in C9orf72 ALS/FTLD. |
| 260 | _ | _ | |a Oxford |c 2017 |b Oxford Univ. Press |
| 264 | _ | 1 | |3 online |2 Crossref |b Oxford University Press (OUP) |c 2016-12-30 |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1590387554_31558 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a A repeat expansion in the non-coding region of C9orf72 gene is the most common mutation causing frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Sense and antisense transcripts are translated into aggregating dipeptide repeat (DPR) proteins in all reading frames (poly-GA,-GP,-GR,-PA and -PR) through an unconventional mechanism. How these changes contribute to cytoplasmic mislocalization and aggregation of TDP-43 and thereby ultimately leading to neuron loss remains unclear. The repeat RNA itself and poly-GR/PR have been linked to impaired nucleocytoplasmic transport. Here, we show that compact cytoplasmic poly-GA aggregates impair nuclear import of a reporter containing the TDP-43 nuclear localization (NLS) signal. However, a reporter containing a non-classical PY-NLS was not affected. Moreover, poly-GA expression prevents TNFα induced nuclear translocation of p65 suggesting that poly-GA predominantly impairs the importin-α/β-dependent pathway. In neurons, prolonged poly-GA expression induces partial mislocalization of TDP-43 into cytoplasmic granules. Rerouting poly-GA to the nucleus prevented TDP-43 mislocalization, suggesting a cytoplasmic mechanism. In rescue experiments, expression of importin-α (KPNA3, KPNA4) or nucleoporins (NUP54, NUP62) restores the nuclear localization of the TDP reporter. Taken together, inhibition of nuclear import of TDP-43 by cytoplasmic poly-GA inclusions causally links the two main aggregating proteins in C9orf72 ALS/FTLD pathogenesis. |
| 536 | _ | _ | |a 342 - Disease Mechanisms and Model Systems (POF3-342) |0 G:(DE-HGF)POF3-342 |c POF3-342 |f POF III |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, |
| 650 | _ | 7 | |a C9orf72 Protein |2 NLM Chemicals |
| 650 | _ | 7 | |a C9orf72 protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a DNA-Binding Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a KPNA3 protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a KPNA4 protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a Membrane Glycoproteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Nuclear Localization Signals |2 NLM Chemicals |
| 650 | _ | 7 | |a Nuclear Pore Complex Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a TDP-43 protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a Tumor Necrosis Factor-alpha |2 NLM Chemicals |
| 650 | _ | 7 | |a alpha Karyopherins |2 NLM Chemicals |
| 650 | _ | 7 | |a nuclear pore protein p62 |2 NLM Chemicals |
| 650 | _ | 2 | |a Amyotrophic Lateral Sclerosis: genetics |2 MeSH |
| 650 | _ | 2 | |a Amyotrophic Lateral Sclerosis: metabolism |2 MeSH |
| 650 | _ | 2 | |a Amyotrophic Lateral Sclerosis: pathology |2 MeSH |
| 650 | _ | 2 | |a Animals |2 MeSH |
| 650 | _ | 2 | |a C9orf72 Protein |2 MeSH |
| 650 | _ | 2 | |a DNA Repeat Expansion |2 MeSH |
| 650 | _ | 2 | |a DNA-Binding Proteins: genetics |2 MeSH |
| 650 | _ | 2 | |a DNA-Binding Proteins: metabolism |2 MeSH |
| 650 | _ | 2 | |a Frontotemporal Lobar Degeneration: genetics |2 MeSH |
| 650 | _ | 2 | |a Frontotemporal Lobar Degeneration: metabolism |2 MeSH |
| 650 | _ | 2 | |a Frontotemporal Lobar Degeneration: pathology |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Inclusion Bodies: genetics |2 MeSH |
| 650 | _ | 2 | |a Inclusion Bodies: metabolism |2 MeSH |
| 650 | _ | 2 | |a Membrane Glycoproteins: genetics |2 MeSH |
| 650 | _ | 2 | |a Membrane Glycoproteins: metabolism |2 MeSH |
| 650 | _ | 2 | |a Neurons: metabolism |2 MeSH |
| 650 | _ | 2 | |a Nuclear Localization Signals: genetics |2 MeSH |
| 650 | _ | 2 | |a Nuclear Localization Signals: metabolism |2 MeSH |
| 650 | _ | 2 | |a Nuclear Pore Complex Proteins: genetics |2 MeSH |
| 650 | _ | 2 | |a Nuclear Pore Complex Proteins: metabolism |2 MeSH |
| 650 | _ | 2 | |a Proteins: genetics |2 MeSH |
| 650 | _ | 2 | |a Proteins: metabolism |2 MeSH |
| 650 | _ | 2 | |a Rats |2 MeSH |
| 650 | _ | 2 | |a Tumor Necrosis Factor-alpha: genetics |2 MeSH |
| 650 | _ | 2 | |a Tumor Necrosis Factor-alpha: metabolism |2 MeSH |
| 650 | _ | 2 | |a alpha Karyopherins: genetics |2 MeSH |
| 650 | _ | 2 | |a alpha Karyopherins: metabolism |2 MeSH |
| 700 | 1 | _ | |a Hartmann, Hannelore |0 P:(DE-2719)2811080 |b 1 |u dzne |
| 700 | 1 | _ | |a May, Stephanie |0 P:(DE-2719)2762699 |b 2 |u dzne |
| 700 | 1 | _ | |a Möhl, Christoph |0 P:(DE-2719)2810422 |b 3 |u dzne |
| 700 | 1 | _ | |a Ederle, Helena |0 P:(DE-HGF)0 |b 4 |
| 700 | 1 | _ | |a Michaelsen, Meike |0 P:(DE-2719)2811691 |b 5 |u dzne |
| 700 | 1 | _ | |a Schludi, Martin H |0 P:(DE-2719)2810746 |b 6 |u dzne |
| 700 | 1 | _ | |a Dormann, Dorothee |0 P:(DE-HGF)0 |b 7 |
| 700 | 1 | _ | |a Edbauer, Dieter |0 P:(DE-2719)2231621 |b 8 |e Last author |u dzne |
| 773 | 1 | 8 | |a 10.1093/hmg/ddw432 |b : Oxford University Press (OUP), 2016-12-30 |p ddw432 |3 journal-article |2 Crossref |t Human Molecular Genetics |y 2016 |x 0964-6906 |
| 773 | _ | _ | |a 10.1093/hmg/ddw432 |g Vol. 26, no. 4, p. ddw432 - |0 PERI:(DE-600)1474816-2 |n 4 |q 26:4 |t Human molecular genetics |v 26 |y 2016 |x 0964-6906 |
| 856 | 7 | _ | |2 Pubmed Central |u http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409121 |
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