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000138124 1001_ $$0P:(DE-2719)2810746$$aSchludi, Martin H$$b0$$eFirst author$$udzne
000138124 245__ $$aDistribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing.
000138124 260__ $$aHeidelberg$$bSpringer$$c2015
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000138124 520__ $$aA massive expansion of a GGGGCC repeat upstream of the C9orf72 coding region is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. Despite its intronic localization and lack of a canonical start codon, both strands are translated into aggregating dipeptide repeat (DPR) proteins: poly-GA, poly-GP, poly-GR, poly-PR and poly-PA. To address conflicting findings on the predominant toxicity of the different DPR species in model systems, we compared the expression pattern of the DPR proteins in rat primary neurons and postmortem brain and spinal cord of C9orf72 mutation patients. Only poly-GA overexpression closely mimicked the p62-positive neuronal cytoplasmic inclusions commonly observed for all DPR proteins in patients. In contrast, overexpressed poly-GR and poly-PR formed nucleolar p62-negative inclusions. In patients, most of the less common neuronal intranuclear DPR inclusions were para-nucleolar and p62 positive. Neuronal nucleoli in C9orf72 cases showed normal size and morphology regardless of the presence of poly-GR and poly-PR inclusions arguing against widespread nucleolar stress, reported in cellular models. Colocalization of para-nucleolar DPR inclusions with heterochromatin and a marker of transcriptional repression (H3K9me2) indicates a link to gene transcription. In contrast, we detected numerous intranuclear DPR inclusions not associated with nucleolar structures in ependymal and subependymal cells. In patients, neuronal inclusions of poly-GR, poly-GP and the poly-GA interacting protein Unc119 were less abundant than poly-GA inclusions, but showed similar regional and subcellular distribution. Regardless of neurodegeneration, all inclusions were most abundant in neocortex, hippocampus and thalamus, with few inclusions in brain stem and spinal cord. In the granular cell layer of the cerebellum, poly-GA and Unc119 inclusions were significantly more abundant in cases with FTLD than in cases with MND and FTLD/MND. Poly-PR inclusions were rare throughout the brain but significantly more abundant in the CA3/4 region of FTLD cases than in MND cases. Thus, although DPR distribution is not correlated with neurodegeneration spatially, it correlates with neuropathological subtypes.
000138124 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
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000138124 542__ $$2Crossref$$i2015-06-18$$uhttp://creativecommons.org/licenses/by/4.0
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000138124 650_7 $$2NLM Chemicals$$aAdaptor Proteins, Signal Transducing
000138124 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000138124 650_7 $$2NLM Chemicals$$aC9orf72 protein, human
000138124 650_7 $$2NLM Chemicals$$aProteins
000138124 650_7 $$2NLM Chemicals$$aUNC119 protein, human
000138124 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: metabolism
000138124 650_2 $$2MeSH$$aAdult
000138124 650_2 $$2MeSH$$aAged
000138124 650_2 $$2MeSH$$aAnimals
000138124 650_2 $$2MeSH$$aBrain: metabolism
000138124 650_2 $$2MeSH$$aBrain: pathology
000138124 650_2 $$2MeSH$$aC9orf72 Protein
000138124 650_2 $$2MeSH$$aCell Nucleolus: metabolism
000138124 650_2 $$2MeSH$$aCell Nucleolus: pathology
000138124 650_2 $$2MeSH$$aCohort Studies
000138124 650_2 $$2MeSH$$aDNA Repeat Expansion
000138124 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: complications
000138124 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: genetics
000138124 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: metabolism
000138124 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: pathology
000138124 650_2 $$2MeSH$$aGene Silencing
000138124 650_2 $$2MeSH$$aHumans
000138124 650_2 $$2MeSH$$aInclusion Bodies: metabolism
000138124 650_2 $$2MeSH$$aInclusion Bodies: pathology
000138124 650_2 $$2MeSH$$aMiddle Aged
000138124 650_2 $$2MeSH$$aMotor Neuron Disease: complications
000138124 650_2 $$2MeSH$$aMotor Neuron Disease: genetics
000138124 650_2 $$2MeSH$$aMotor Neuron Disease: metabolism
000138124 650_2 $$2MeSH$$aMotor Neuron Disease: pathology
000138124 650_2 $$2MeSH$$aNeuroglia: metabolism
000138124 650_2 $$2MeSH$$aNeuroglia: pathology
000138124 650_2 $$2MeSH$$aNeurons: metabolism
000138124 650_2 $$2MeSH$$aNeurons: pathology
000138124 650_2 $$2MeSH$$aProteins: genetics
000138124 650_2 $$2MeSH$$aProteins: metabolism
000138124 650_2 $$2MeSH$$aRats
000138124 650_2 $$2MeSH$$aSpinal Cord: metabolism
000138124 650_2 $$2MeSH$$aSpinal Cord: pathology
000138124 7001_ $$0P:(DE-2719)2762699$$aMay, Stephanie$$b1$$udzne
000138124 7001_ $$aGrässer, Friedrich A$$b2
000138124 7001_ $$0P:(DE-2719)2501892$$aRentzsch, Kristin$$b3$$udzne
000138124 7001_ $$0P:(DE-2719)9000167$$aKremmer, Elisabeth$$b4$$udzne
000138124 7001_ $$0P:(DE-2719)9000175$$aKüpper, Clemens$$b5$$udzne
000138124 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b6$$udzne
000138124 7001_ $$aDegeneration, German Consortium for Frontotemporal Lobar$$b7
000138124 7001_ $$aAlliance, Bavarian Brain Banking$$b8
000138124 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b9$$eCorresponding author$$udzne
000138124 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b10$$eLast author$$udzne
000138124 7001_ $$0P:(DE-HGF)0$$aDanek, Adrian$$b11
000138124 7001_ $$0P:(DE-HGF)0$$aDiehl-Schmid, Janine$$b12
000138124 7001_ $$aFassbender, Klaus$$b13
000138124 7001_ $$aFörstl, Hans$$b14
000138124 7001_ $$aKornhuber, Johannes$$b15
000138124 7001_ $$aOtto, Markus$$b16
000138124 7001_ $$aCeballos-Baumann, Andres$$b17
000138124 7001_ $$0P:(DE-HGF)0$$aDieterich, Marianne$$b18
000138124 7001_ $$aFeuerecker, Regina$$b19
000138124 7001_ $$0P:(DE-HGF)0$$aGiese, Armin$$b20
000138124 7001_ $$aKlünemann, Hans$$b21
000138124 7001_ $$aKurz, Alexander$$b22
000138124 7001_ $$0P:(DE-HGF)0$$aLevin, Johannes$$b23
000138124 7001_ $$aLorenzl, Stefan$$b24
000138124 7001_ $$aMeyer, Thomas$$b25
000138124 7001_ $$aNübling, Georg$$b26
000138124 7001_ $$aRoeber, Sigrun$$b27
000138124 77318 $$2Crossref$$3journal-article$$a10.1007/s00401-015-1450-z$$b : Springer Science and Business Media LLC, 2015-06-18$$n4$$p537-555$$tActa Neuropathologica$$v130$$x0001-6322$$y2015
000138124 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-015-1450-z$$gVol. 130, no. 4, p. 537 - 555$$n4$$p537-555$$q130:4<537 - 555$$tActa neuropathologica$$v130$$x0001-6322$$y2015
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