Abstract
Frontotemporal dementia and amyotrophic lateral sclerosis patients with C9orf72 mutation show cytoplasmic poly-GR and poly-PR aggregates. Short poly-(Gly-Arg) and poly-(Pro-Arg) (poly-GR/PR) repeats localizing to the nucleolus are toxic in various model systems, but no interactors have been validated in patients. Here, the neuronal interactomes of cytoplasmic GFP-(GR)149 and nucleolar (PR)175-GFP revealed overlapping RNA-binding proteins, including components of stress granules, nucleoli, and ribosomes. Overexpressing the poly-GR/PR interactors STAU1/2 and YBX1 caused cytoplasmic aggregation of poly-GR/PR in large stress granule-like structures, whereas NPM1 recruited poly-GR into the nucleolus. Poly-PR expression reduced ribosome levels and translation consistent with reduction of synaptic proteins detected by proteomics. Surprisingly, truncated GFP-(GR)53, but not GFP-(GR)149, localized to the nucleolus and reduced ribosome levels and translation similar to poly-PR, suggesting that impaired ribosome biogenesis may be driving the acute toxicity observed in vitro. In patients, only ribosomes and STAU2 co-aggregated with poly-GR/PR. Partial sequestration of ribosomes may chronically impair protein synthesis even in the absence of nucleolar localization and contribute to pathogenesis.
Highlights
Since the discovery of the (GGGGCC)n repeat expansion in C9orf72 in about 10% of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia patients, several potential pathomechanisms have been proposed (Edbauer & Haass, 2016)
Sense and antisense transcripts of the repeat are translated into five dipeptide repeat (DPR) proteins that coaggregate in predominantly neuronal cytoplasmic inclusions in C9orf72 patients: poly-GA, poly-GP, poly-GR, poly-PR, and poly-PA
Several hypotheses have been put forward to explain the toxicity of arginine-rich DPR proteins in various model systems, including impaired nucleocytoplasmic transport (Jovicic et al, 2015), oxidative stress (Lopez-Gonzalez et al, 2016), interference with membrane-less organelles (Lee et al, 2016; Lin et al, 2016; Boeynaems et al, 2017), impaired splicing (Kwon et al, 2014; Lin et al, 2016), and translation (Kanekura et al, 2016)
Summary
Since the discovery of the (GGGGCC)n repeat expansion in C9orf in about 10% of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia patients, several potential pathomechanisms have been proposed (Edbauer & Haass, 2016). The repeat RNA is clustered in nuclear foci in neurons and non-neuronal tissues in patients, without apparent correlation with neuron loss (DeJesusHernandez et al, 2017). Several proteins binding to the repeat RNA have been identified, but up to now their role in pathogenesis is still unclear. Several groups failed to detect a direct correlation of DPR expression with neurodegeneration (Mackenzie et al, 2013, 2015; Schludi et al, 2015), a recent report identified dendritic poly-GR pathology in the motor cortex of ALS patients (Saberi et al, 2018), it is unclear how the conflicting findings can be explained. The role of the DPR proteins in disease pathogenesis is still under intense debate
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