Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Abstract

The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

Fig. 1

RNA dysfunction in amyotrophic lateral sclerosis (ALS). Abnormal accumulation or localization of the RNA binding proteins transactive response element DNA/RNA binding protein of 43 kDa (TDP43) or fused in sarcoma (FUS) can affect (1) global splicing machinery and (2) gene expression. (3) In addition, these proteins associate with microRNA (miRNA) assembly machinery, and changes in their levels or distribution are likely to affect the processing of miRNAs and other noncoding regulatory RNAs. (4) Hexanucleotide G₄C₂ repeats in C9orf72 form G-quadruplex secondary structures that sequester essential nuclear RNA-binding proteins (RBPs). (5) C9orf72 G₄C₂ repeats are also translated through repeat-associated non-AUG (RAN) translation, and the resulting dipeptides may have direct neurotoxic effects. (6) TDP43 and FUS participate in the formation of RNA-rich stress granules, and can disrupt physiologic stress granule assembly or disassembly. (7) Abnormal stress granule kinetics may result in the abnormal sequestration of bound RNAs and associated RBPs, and (8) facilitate the irreversible formation of insoluble protein aggregates that are a characteristic feature of ALS