TY  - JOUR
AU  - Mori, Kohji
AU  - Nihei, Yoshihiro
AU  - Arzberger, Thomas
AU  - Zhou, Qihui
AU  - Mackenzie, Ian R
AU  - Hermann, Andreas
AU  - Hanisch, Frank
AU  - Degeneration, German Consortium for Frontotemporal Lobar
AU  - Alliance, Bavarian Brain Banking
AU  - Kamp, Frits
AU  - Nuscher, Brigitte
AU  - Orozco, Denise
AU  - Edbauer, Dieter
AU  - Haass, Christian
TI  - Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition.
JO  - EMBO reports
VL  - 17
IS  - 9
SN  - 1469-221X
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2020-05095
SP  - 1314-1325
PY  - 2016
AB  - Intronic hexanucleotide (G4C2) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins (DPR). Repeat-dependent toxicity may affect nuclear import. hnRNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G4C2 repeat RNA We now report that a reduction of nuclear hnRNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hnRNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hnRNPA3. Reduced nuclear hnRNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci.
KW  - Animals
KW  - Brain: metabolism
KW  - C9orf72 Protein
KW  - Dipeptides: metabolism
KW  - Fibroblasts
KW  - Gene Expression Regulation
KW  - Gene Knockdown Techniques
KW  - HeLa Cells
KW  - Heterogeneous-Nuclear Ribonucleoprotein Group A-B: metabolism
KW  - Humans
KW  - Neurons: metabolism
KW  - Protein Binding
KW  - Protein Transport
KW  - Proteins: genetics
KW  - Pyramidal Cells: metabolism
KW  - RNA Transport
KW  - RNA, Messenger: genetics
KW  - RNA, Small Interfering: genetics
KW  - Rats
KW  - C9orf72 Protein (NLM Chemicals)
KW  - C9orf72 protein, human (NLM Chemicals)
KW  - Dipeptides (NLM Chemicals)
KW  - HNRNPA3 protein, human (NLM Chemicals)
KW  - Heterogeneous-Nuclear Ribonucleoprotein Group A-B (NLM Chemicals)
KW  - Proteins (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - RNA, Small Interfering (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27461252
C2  - pmc:PMC5007570
DO  - DOI:10.15252/embr.201541724
UR  - https://pub.dzne.de/record/138773
ER  -