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| Home > Publications Database > Cytoplasmic poly-GA aggregates impair nuclear import of TDP-43 in C9orf72 ALS/FTLD. |
| Home > Publications Database > Cytoplasmic poly-GA aggregates impair nuclear import of TDP-43 in C9orf72 ALS/FTLD. |
| Journal Article | DZNE-2020-05449 |
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2017
Oxford Univ. Press
Oxford
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Please use a persistent id in citations: doi:10.1093/hmg/ddw432
Abstract: 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.
Keyword(s): Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Animals (MeSH) ; C9orf72 Protein (MeSH) ; DNA Repeat Expansion (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; Frontotemporal Lobar Degeneration: genetics (MeSH) ; Frontotemporal Lobar Degeneration: metabolism (MeSH) ; Frontotemporal Lobar Degeneration: pathology (MeSH) ; Humans (MeSH) ; Inclusion Bodies: genetics (MeSH) ; Inclusion Bodies: metabolism (MeSH) ; Membrane Glycoproteins: genetics (MeSH) ; Membrane Glycoproteins: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Nuclear Localization Signals: genetics (MeSH) ; Nuclear Localization Signals: metabolism (MeSH) ; Nuclear Pore Complex Proteins: genetics (MeSH) ; Nuclear Pore Complex Proteins: metabolism (MeSH) ; Proteins: genetics (MeSH) ; Proteins: metabolism (MeSH) ; Rats (MeSH) ; Tumor Necrosis Factor-alpha: genetics (MeSH) ; Tumor Necrosis Factor-alpha: metabolism (MeSH) ; alpha Karyopherins: genetics (MeSH) ; alpha Karyopherins: metabolism (MeSH) ; C9orf72 Protein ; C9orf72 protein, human ; DNA-Binding Proteins ; KPNA3 protein, human ; KPNA4 protein, human ; Membrane Glycoproteins ; Nuclear Localization Signals ; Nuclear Pore Complex Proteins ; Proteins ; TDP-43 protein, human ; Tumor Necrosis Factor-alpha ; alpha Karyopherins ; nuclear pore protein p62
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