Abstract
The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1336-5) contains supplementary material, which is available to authorized users.
Highlights
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders
Since cell death associated with the PERK–C/EBP homologous protein (CHOP) signaling pathway is partially mediated through the dephosphorylation of eukaryotic translation initiation factor 2α, which is regulated by the association of growth arrest and DNA damage inducible 34 (GADD34) with protein phosphatase 1 (PP1C) [24, 25, 42, 49], we examined the phosphorylation status of eIF2α in neurons expressing GFP-(GA)50
While each c9RAN protein may influence neuronal health differently, we provide evidence that poly(GA) proteins are neurotoxic and could be implicated in the neurodegenerative processes of c9FTD/ALS
Summary
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders. Despite the fact that FTD presents with changes in behavior, personality and language and ALS is a motor neuron disease which leads to progressive paralysis, there is genetic, neuropathological and clinical overlap between them. FTD-like cognitive and behavioral impairments [22, 39, 54], and as many as half of FTD patients develop motor neuron dysfunction [39]. Neuronal and glial inclusions of TDP-43 are found in most ALS cases, as well as in the most common pathological subtype of FTD [frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP)]. Because of this overlap, ALS and FTLD-TDP are considered part of a disease spectrum. This concept was recently reinforced with the discovery that a G4C2·G2C4 repeat expansion in a non-coding region of the C9ORF72 gene is the most common genetic cause of ALS and FTLD-TDP [14, 41, 58]
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