(A) RNA-binding proteins (red, green, orange, purple, and blue), such as TDP-43 (green), regulate various RNA processing pathways, like the alternative splicing of mRNA. Many of these proteins are also prone to aggregating and becoming insoluble. As represented by the seesaw, this means that their concentration, solubility, and interactions with proteins must be controlled to maintain balance in the cell (right). Under normal conditions, TDP-43 is soluble and is mainly localized in the nucleus of the cell. (B) A mutation in a gene called C9orf72 can result in a reduction in the solubility of an RNA-binding protein known as hnRNP H (purple). This can also lead to changes in the concentration and solubility of other RNA-binding proteins (including TDP-43), which disrupts alternative splicing and other processes in the cell. The reduction in the solubility of TDP-43 causes it to accumulate in the cytoplasm, which is a hallmark of ALS and FTD. (C) Other triggers, such as genetic and environmental factors, can change the concentration and solubility of RNA-binding proteins (unbalanced seesaw); this causes them to misfold, become insoluble and accumulate in the cytoplasm.