TY  - JOUR
AU  - Schludi, Martin H
AU  - May, Stephanie
AU  - Grässer, Friedrich A
AU  - Rentzsch, Kristin
AU  - Kremmer, Elisabeth
AU  - Küpper, Clemens
AU  - Klopstock, Thomas
AU  - Degeneration, German Consortium for Frontotemporal Lobar
AU  - Alliance, Bavarian Brain Banking
AU  - Arzberger, Thomas
AU  - Edbauer, Dieter
AU  - Danek, Adrian
AU  - Diehl-Schmid, Janine
AU  - Fassbender, Klaus
AU  - Förstl, Hans
AU  - Kornhuber, Johannes
AU  - Otto, Markus
AU  - Ceballos-Baumann, Andres
AU  - Dieterich, Marianne
AU  - Feuerecker, Regina
AU  - Giese, Armin
AU  - Klünemann, Hans
AU  - Kurz, Alexander
AU  - Levin, Johannes
AU  - Lorenzl, Stefan
AU  - Meyer, Thomas
AU  - Nübling, Georg
AU  - Roeber, Sigrun
TI  - Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing.
JO  - Acta neuropathologica
VL  - 130
IS  - 4
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2020-04446
SP  - 537-555
PY  - 2015
AB  - A 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.
KW  - Adaptor Proteins, Signal Transducing: metabolism
KW  - Adult
KW  - Aged
KW  - Animals
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - C9orf72 Protein
KW  - Cell Nucleolus: metabolism
KW  - Cell Nucleolus: pathology
KW  - Cohort Studies
KW  - DNA Repeat Expansion
KW  - Frontotemporal Lobar Degeneration: complications
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Frontotemporal Lobar Degeneration: pathology
KW  - Gene Silencing
KW  - Humans
KW  - Inclusion Bodies: metabolism
KW  - Inclusion Bodies: pathology
KW  - Middle Aged
KW  - Motor Neuron Disease: complications
KW  - Motor Neuron Disease: genetics
KW  - Motor Neuron Disease: metabolism
KW  - Motor Neuron Disease: pathology
KW  - Neuroglia: metabolism
KW  - Neuroglia: pathology
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Proteins: genetics
KW  - Proteins: metabolism
KW  - Rats
KW  - Spinal Cord: metabolism
KW  - Spinal Cord: pathology
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
KW  - C9orf72 Protein (NLM Chemicals)
KW  - C9orf72 protein, human (NLM Chemicals)
KW  - Proteins (NLM Chemicals)
KW  - UNC119 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26085200
C2  - pmc:PMC4575390
DO  - DOI:10.1007/s00401-015-1450-z
UR  - https://pub.dzne.de/record/138124
ER  -