Details

Autor(en) / Beteiligte

• Zhang, Yong-Jie
• Gendron, Tania F
• Ebbert, Mark T W
• O'Raw, Aliesha D
• Yue, Mei
• Jansen-West, Karen
• Zhang, Xu
• Prudencio, Mercedes
• Chew, Jeannie
• Cook, Casey N
• Daughrity, Lillian M
• Tong, Jimei
• Song, Yuping
• Pickles, Sarah R
• Castanedes-Casey, Monica
• Kurti, Aishe
• Rademakers, Rosa
• Oskarsson, Bjorn
• Dickson, Dennis W
• Hu, Wenqian
• Gitler, Aaron D
• Fryer, John D
• Petrucelli, Leonard

Titel

Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Ist Teil von

• Nature medicine, 2018-08, Vol.24 (8), p.1136-1142

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 G C repeat expansion . Proposed mechanisms by which the expansion causes c9FTD/ALS include toxicity from repeat-containing RNA and from dipeptide repeat proteins translated from these transcripts. To investigate the contribution of poly(GR) dipeptide repeat proteins to c9FTD/ALS pathogenesis in a mammalian in vivo model, we generated mice that expressed GFP-(GR) in the brain. GFP-(GR) mice developed age-dependent neurodegeneration, brain atrophy, and motor and memory deficits through the accumulation of diffuse, cytoplasmic poly(GR). Poly(GR) co-localized with ribosomal subunits and the translation initiation factor eIF3η in GFP-(GR) mice and, of importance, in c9FTD/ALS patients. Combined with the differential expression of ribosome-associated genes in GFP-(GR) mice, these findings demonstrate poly(GR)-mediated ribosomal distress. Indeed, poly(GR) inhibited canonical and non-canonical protein translation in HEK293T cells, and also induced the formation of stress granules and delayed their disassembly. These data suggest that poly(GR) contributes to c9FTD/ALS by impairing protein translation and stress granule dynamics, consequently causing chronic cellular stress and preventing cells from mounting an effective stress response. Decreasing poly(GR) and/or interrupting interactions between poly(GR) and ribosomal and stress granule-associated proteins may thus represent potential therapeutic strategies to restore homeostasis.