Journal Article

DZNE-2020-05095

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition.

Mori, K. (Corresponding author) ; Nihei, Y. ; Arzberger, T.DZNE* ; Zhou, Q.DZNE* ; Mackenzie, I. R. ; Hermann, A.DZNE* ; Hanisch, F. ; Degeneration, G. C. f. F. L. ; Alliance, B. B. B. ; Kamp, F. ; Nuscher, B. ; Orozco, D.DZNE* ; Edbauer, D.DZNE* ; Haass, C. (Last author)DZNE*

2016
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.15252/embr.201541724

Abstract: 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.

Keyword(s): Animals (MeSH) ; Brain: metabolism (MeSH) ; C9orf72 Protein (MeSH) ; Dipeptides: metabolism (MeSH) ; Fibroblasts (MeSH) ; Gene Expression Regulation (MeSH) ; Gene Knockdown Techniques (MeSH) ; HeLa Cells (MeSH) ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B: metabolism (MeSH) ; Humans (MeSH) ; Neurons: metabolism (MeSH) ; Protein Binding (MeSH) ; Protein Transport (MeSH) ; Proteins: genetics (MeSH) ; Pyramidal Cells: metabolism (MeSH) ; RNA Transport (MeSH) ; RNA, Messenger: genetics (MeSH) ; RNA, Small Interfering: genetics (MeSH) ; Rats (MeSH) ; C9orf72 Protein ; C9orf72 protein, human ; Dipeptides ; HNRNPA3 protein, human ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B ; Proteins ; RNA, Messenger ; RNA, Small Interfering

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Contributing Institute(s):

1. Clinical Neurodegeneration (AG Levin)
2. Cell Biology of Neurodegeneration (AG Edbauer)
3. Molecular Neurodegeneration (AG Haass)
4. Clinical Dementia Research (Rostock /Greifswald) (AG Teipel)
5. Adaptive Immunity in Neurodegeneration (AG Zhou)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)
2. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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