C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo

• Published in: Nature neuroscience Vol. 22; no. 6; pp. 851 - 862
• Main Authors: Choi, So Yoen, Lopez-Gonzalez, Rodrigo, Krishnan, Gopinath, Phillips, Hannah L., Li, Alissa Nana, Seeley, William W., Yao, Wei-Dong, Almeida, Sandra, Gao, Fen-Biao
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2019; Nature Publishing Group
• Subjects: 13/106; 13/51; 14/19; 14/28; 38/35; 38/77; 631/378/1689/1285; 631/378/1689/132; 64/110; 64/60; 82/29; 82/80; Abnormalities; Age; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - physiopathology; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biocompatibility; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; C9orf72 Protein - genetics; Complications and side effects; Cortex; Defects; Dementia disorders; Deoxyribonucleic acid; Development and progression; Disease Models, Animal; DNA; DNA damage; DNA Repeat Expansion; Frontotemporal dementia; Frontotemporal Dementia - genetics; Frontotemporal Dementia - physiopathology; Genetic aspects; Health aspects; Humans; Mice; Mice, Transgenic; Mitochondria; Mitochondria - pathology; Mitochondrial diseases; Mitochondrial Proton-Translocating ATPases - metabolism; Neurobiology; Neurons; Neurons - metabolism; Neurosciences; Neurotoxicity; Toxicity; Trinucleotide repeats; Ubiquitination
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-019-0397-0

The GGGGCC repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it is not known which dysregulated molecular pathways are primarily responsible for disease initiation or progression. We established an inducible mouse model of poly(GR) toxicity in which (GR) 80 gradually accumulates in cortical excitatory neurons. Low-level poly(GR) expression induced FTD/ALS-associated synaptic dysfunction and behavioral abnormalities, as well as age-dependent neuronal cell loss, microgliosis and DNA damage, probably caused in part by early defects in mitochondrial function. Poly(GR) bound preferentially to the mitochondrial complex V component ATP5A1 and enhanced its ubiquitination and degradation, consistent with reduced ATP5A1 protein level in both (GR) 80 mouse neurons and patient brains. Moreover, inducing ectopic Atp5a1 expression in poly(GR)-expressing neurons or reducing poly(GR) level in adult mice after disease onset rescued poly(GR)-induced neurotoxicity. Thus, poly(GR)-induced mitochondrial defects are a major driver of disease initiation in C9ORF72 -related ALS/FTD. The authors generated a mouse model of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia based on dipeptide repeat proteins and report that defects in mitochondria may contribute to disease pathogenesis.