RNA Dysfunction and RNA binding Proteins in the Syndrome of ALS/FTD

RNA dysfunction and abnormal intracellular aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The discoveries with the identification of new genes as major genetic causes of ALS/FTD syndromes reinforce the genetic, clinical and pathological overlap between ALS and FTD. Common causes of these diseases include mutations in the RNA/DNA-binding proteins, TDP-43 and FUS and most recently, GGGGCC hexanucleotide expansions in the C9orf72 gene. TDP-43 and FUS are both RNA processing proteins whose dysfunction impacts on global cellular RNA regulation, and are both abnormally aggregated and mislocalized in ALS and FTD, while The expression of repeat expansions in the C9orf72 gene may induce RNA foci that could sequester RNA binding proteins such as Pur α and hnRNP A3 highlights a further possibly important mechanism of RNA dysfunction in disease. Furthermore, sequestration of key RNA binding proteins may also play an important role in ALS/FTD syndromes due to the association of TDP-43 and FUS with stress granules. In this review we discuss the importance of RNA dysfunction and RNA binding proteins and suggest mechanisms by which they may cause ALS/FTD.