RNA-Binding Proteins and the Complex Pathophysiology of ALS.

Wanil Kim,Do-Yeon Kim,Kyung-Ha Lee

doi:10.3390/ijms22052598

Abstract

Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have identified disease-causing mutations and accelerated the unveiling of complex molecular pathogenic mechanisms, which may be important for understanding the disease and developing therapeutic strategies. Many disease-related genes encode RNA-binding proteins, and most of the disease-causing RNA or proteins encoded by these genes form aggregates and disrupt cellular function related to RNA metabolism. Disease-related RNA or proteins interact or sequester other RNA-binding proteins. Eventually, many disease-causing mutations lead to the dysregulation of nucleocytoplasmic shuttling, the dysfunction of stress granules, and the altered dynamic function of the nucleolus as well as other membrane-less organelles. As RNA-binding proteins are usually components of several RNA-binding protein complexes that have other roles, the dysregulation of RNA-binding proteins tends to cause diverse forms of cellular dysfunction. Therefore, understanding the role of RNA-binding proteins will help elucidate the complex pathophysiology of ALS. Here, we summarize the current knowledge regarding the function of disease-associated RNA-binding proteins and their role in the dysfunction of membrane-less organelles.

Highlights

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Repeat-containing transcripts of the mutated chromosome 9 open reading frame 72 (C9orf72) gene can form RNA foci enriched with RNA-binding proteins in induced pluripotent stem cell-derived neurons from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, as well as in motor neurons of C9orf72-ALS patients [37,38,39,40]
Studies demonstrating the mechanisms of toxicity of Dipeptide repeat (DPR) in vitro and in Drosophila revealed that poly-GR and poly-PR DPRs interact with RNA-binding proteins or proteins that contain a low complexity sequence domain (LCD), called the prion-like domain [47,48]

Summary

RNA-Binding Proteins and ALS

In 1939, the major league baseball player Lou Gehrig was diagnosed with amyotrophic lateral sclerosis (ALS), which is often called Lou Gehrig’s disease. ALS-causative mutations in FUS or TARDBP show abnormal stress granule formation with defects in translation, the formation of pathogenic RNA foci, the dysregulation of nucleocytoplasmic shuttling, as well as other forms of disrupted RNA metabolism [32,33]. The ALS-associated RNA-binding protein Matrin-3 (MATR3) was found to colocalize with GGGGCC RNA foci in patient tissues as well as iPSC-derived motor neurons harboring the C9orf mutation. C9orf72-derived DPR poly-GR and poly-PR have been shown to interact with several mediators of nucleocytoplasmic shuttling, including IPO5, IPO7, KPNA2, KPNB1, NUP205, XPO1, and TNPO1, as well as with RNA-binding proteins consisting of nuclear pore complexes, such as PARP1, YBX1, and LBR [47]. The modulation of actin homeostasis rescues nuclear pore instability and the dysfunction of RNA-binding proteins mediated by C9orf repeat expansion or mutant PFN1 [80]

RNA-Binding Protein and Stress Granule Formation

RNA-Binding Protein with Dysfunction of the Nucleolus and Cajal Bodies

Findings

Conclusions and Future Directions