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Reduced hn RNPA 3 increases C9orf72 repeat RNA levels and dipeptide‐repeat protein deposition
Author(s) -
Mori Kohji,
Nihei Yoshihiro,
Arzberger Thomas,
Zhou Qihui,
Mackenzie Ian R,
Hermann Andreas,
Hanisch Frank,
Kamp Frits,
Nuscher Brigitte,
Orozco Denise,
Edbauer Dieter,
Haass Christian
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201541724
Subject(s) - rna , chemistry , microbiology and biotechnology , biology , biochemistry , gene
Intronic hexanucleotide (G 4 C 2 ) 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. hn RNPA 3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G 4 C 2 repeat RNA . We now report that a reduction of nuclear hn RNPA 3 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 hn RNPA 3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hn RNPA 3. Reduced nuclear hn RNPA 3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hn RNPA 3 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.