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000139127 0247_ $$2doi$$a10.1093/hmg/ddw432
000139127 0247_ $$2pmid$$apmid:28040728
000139127 0247_ $$2pmc$$apmc:PMC5409121
000139127 0247_ $$2ISSN$$a0964-6906
000139127 0247_ $$2ISSN$$a1460-2083
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000139127 037__ $$aDZNE-2020-05449
000139127 041__ $$aEnglish
000139127 082__ $$a570
000139127 1001_ $$0P:(DE-2719)2811528$$aKhosravi, Bahram$$b0$$eFirst author$$udzne
000139127 245__ $$aCytoplasmic poly-GA aggregates impair nuclear import of TDP-43 in C9orf72 ALS/FTLD.
000139127 260__ $$aOxford$$bOxford Univ. Press$$c2017
000139127 264_1 $$2Crossref$$3online$$bOxford University Press (OUP)$$c2016-12-30
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000139127 520__ $$aA repeat expansion in the non-coding region of C9orf72 gene is the most common mutation causing frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Sense and antisense transcripts are translated into aggregating dipeptide repeat (DPR) proteins in all reading frames (poly-GA,-GP,-GR,-PA and -PR) through an unconventional mechanism. How these changes contribute to cytoplasmic mislocalization and aggregation of TDP-43 and thereby ultimately leading to neuron loss remains unclear. The repeat RNA itself and poly-GR/PR have been linked to impaired nucleocytoplasmic transport. Here, we show that compact cytoplasmic poly-GA aggregates impair nuclear import of a reporter containing the TDP-43 nuclear localization (NLS) signal. However, a reporter containing a non-classical PY-NLS was not affected. Moreover, poly-GA expression prevents TNFα induced nuclear translocation of p65 suggesting that poly-GA predominantly impairs the importin-α/β-dependent pathway. In neurons, prolonged poly-GA expression induces partial mislocalization of TDP-43 into cytoplasmic granules. Rerouting poly-GA to the nucleus prevented TDP-43 mislocalization, suggesting a cytoplasmic mechanism. In rescue experiments, expression of importin-α (KPNA3, KPNA4) or nucleoporins (NUP54, NUP62) restores the nuclear localization of the TDP reporter. Taken together, inhibition of nuclear import of TDP-43 by cytoplasmic poly-GA inclusions causally links the two main aggregating proteins in C9orf72 ALS/FTLD pathogenesis.
000139127 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
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000139127 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000139127 650_7 $$2NLM Chemicals$$aC9orf72 protein, human
000139127 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000139127 650_7 $$2NLM Chemicals$$aKPNA3 protein, human
000139127 650_7 $$2NLM Chemicals$$aKPNA4 protein, human
000139127 650_7 $$2NLM Chemicals$$aMembrane Glycoproteins
000139127 650_7 $$2NLM Chemicals$$aNuclear Localization Signals
000139127 650_7 $$2NLM Chemicals$$aNuclear Pore Complex Proteins
000139127 650_7 $$2NLM Chemicals$$aProteins
000139127 650_7 $$2NLM Chemicals$$aTDP-43 protein, human
000139127 650_7 $$2NLM Chemicals$$aTumor Necrosis Factor-alpha
000139127 650_7 $$2NLM Chemicals$$aalpha Karyopherins
000139127 650_7 $$2NLM Chemicals$$anuclear pore protein p62
000139127 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000139127 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000139127 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000139127 650_2 $$2MeSH$$aAnimals
000139127 650_2 $$2MeSH$$aC9orf72 Protein
000139127 650_2 $$2MeSH$$aDNA Repeat Expansion
000139127 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000139127 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000139127 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: genetics
000139127 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: metabolism
000139127 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: pathology
000139127 650_2 $$2MeSH$$aHumans
000139127 650_2 $$2MeSH$$aInclusion Bodies: genetics
000139127 650_2 $$2MeSH$$aInclusion Bodies: metabolism
000139127 650_2 $$2MeSH$$aMembrane Glycoproteins: genetics
000139127 650_2 $$2MeSH$$aMembrane Glycoproteins: metabolism
000139127 650_2 $$2MeSH$$aNeurons: metabolism
000139127 650_2 $$2MeSH$$aNuclear Localization Signals: genetics
000139127 650_2 $$2MeSH$$aNuclear Localization Signals: metabolism
000139127 650_2 $$2MeSH$$aNuclear Pore Complex Proteins: genetics
000139127 650_2 $$2MeSH$$aNuclear Pore Complex Proteins: metabolism
000139127 650_2 $$2MeSH$$aProteins: genetics
000139127 650_2 $$2MeSH$$aProteins: metabolism
000139127 650_2 $$2MeSH$$aRats
000139127 650_2 $$2MeSH$$aTumor Necrosis Factor-alpha: genetics
000139127 650_2 $$2MeSH$$aTumor Necrosis Factor-alpha: metabolism
000139127 650_2 $$2MeSH$$aalpha Karyopherins: genetics
000139127 650_2 $$2MeSH$$aalpha Karyopherins: metabolism
000139127 7001_ $$0P:(DE-2719)2811080$$aHartmann, Hannelore$$b1$$udzne
000139127 7001_ $$0P:(DE-2719)2762699$$aMay, Stephanie$$b2$$udzne
000139127 7001_ $$0P:(DE-2719)2810422$$aMöhl, Christoph$$b3$$udzne
000139127 7001_ $$0P:(DE-HGF)0$$aEderle, Helena$$b4
000139127 7001_ $$0P:(DE-2719)2811691$$aMichaelsen, Meike$$b5$$udzne
000139127 7001_ $$0P:(DE-2719)2810746$$aSchludi, Martin H$$b6$$udzne
000139127 7001_ $$0P:(DE-HGF)0$$aDormann, Dorothee$$b7
000139127 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b8$$eLast author$$udzne
000139127 77318 $$2Crossref$$3journal-article$$a10.1093/hmg/ddw432$$b : Oxford University Press (OUP), 2016-12-30$$pddw432$$tHuman Molecular Genetics$$x0964-6906$$y2016
000139127 773__ $$0PERI:(DE-600)1474816-2$$a10.1093/hmg/ddw432$$gVol. 26, no. 4, p. ddw432 -$$n4$$pddw432$$q26:4<ddw432 -$$tHuman molecular genetics$$v26$$x0964-6906$$y2016
000139127 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409121
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