Abstract
A GGGGCC repeat expansion in the C9ORF72 gene has been identified as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeat expansion undergoes unconventional translation to produce dipeptide repeat (DPR) proteins. Although it has been reported that DPR proteins cause neurotoxicity, the underlying mechanism has not been fully elucidated. In this study, we have first confirmed that proline–arginine repeat protein (poly-PR) reduces levels of ribosomal RNA and causes neurotoxicity and found that the poly-PR-induced neurotoxicity is repressed by the acceleration of ribosomal RNA synthesis. These results suggest that the poly-PR-induced inhibition of ribosome biogenesis contributes to the poly-PR-induced neurotoxicity. We have further identified DEAD-box RNA helicases as poly-PR-binding proteins, the functions of which are inhibited by poly-PR. The enforced reduction in the expression of DEAD-box RNA helicases causes impairment of ribosome biogenesis and neuronal cell death. These results together suggest that poly-PR causes neurotoxicity by inhibiting the DEAD-box RNA helicase-mediated ribosome biogenesis.
Highlights
Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease, characterized by a selective loss of both upper and lower motor neurons[1,2]
We further found that poly-PR interacted with multiple DEAD-box RNA helicases and inhibited the function of at least one of them, and that the reduction in the levels of some RNA helicases resulted in both the decrease in ribosomal RNA (rRNA) levels and the increase in neuronal cell death
Because our previous studies have shown that the TDP-43-induced apoptosis is mediated by several cell death signals involving c-Jun Nterminal kinase (JNK)/c-Jun, C/EBP homologous protein (CHOP), and Bcl-2-related BH3-only protein Bcl-2interacting mediator of cell death (Bim)[25,26,27], we examined whether the poly-PR-induced neuronal cell death is mediated with these molecules
Summary
Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease, characterized by a selective loss of both upper and lower motor neurons[1,2]. Suzuki et al Cell Death and Disease (2018)9:975 enforced expression of any of DPR proteins likely causes neuronal toxicity in vitro and in vivo[13]. RNA helicases are highly conserved enzymes that play essential roles in most aspects of mRNA metabolism and ribosome biogenesis[14,15,16]. They remodel RNA and ribonucleoprotein complexes mainly by unwinding RNA duplexes in an ATP-dependent fashion. DDX21 shows ATPindependent strand-annealing activity during RNA folding[18] As their activities are essential in various cellular processes, the malfunction of RNA helicases is likely linked to human diseases such as cancer and neurological disorders[19]. The functions of most RNA helicases have been insufficiently characterized
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