RNA binding proteins and protein binding RNAs in ALS and FTD

GGGGCC hexanucleotide repeat expansion mutation (HREM) in non-coding region of C9ORF72 gene has recently been identified as the most common genetic cause of devastating incurable neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The disease relevant function of mutation is not clear. HREM may enable the formation of complex DNA and RNA structures, changes in RNA transcription and processing and formation of toxic RNA foci, which may sequester and inactivate RNA binding proteins. This complexity is further increased by the fact that expanded repeat is also transcribed in the antisense direction forming the CCCCGG (C4G2) repeat. According to some reports the antisense HREM transcript is even more abundant than the sense transcript. Additionally, the transcribed expanded repeats from both directions can undergo repeat-associated non-ATG-initiated (RAN) translation resulting in accumulation and aggregation of a series of dipeptide repeat proteins. Finally, HREM may also lead to haploinsufficiency of the C9orf72 protein. RNA pull-down study identifying some of the binding partners of GGGGCC repeat will be presented along with structural studies of the repeat DNA, which forms G-quadruplex structures.