Protein and non-coding RNA interactions in neurological diseases FXTAS and ALS

Fragile X-associated tremor ataxia (FXTAS) and amyotrophic lateral sclerosis (ALS) are human neurological diseases characterized by neuromuscular and cognitive decline. FXTAS is directly linked to expansion of CGG trinucleotide repeats in the promoter region of FMR1 gene which encodes the Fragile X mental retardation protein FMRP. ALS is predominantly sporadic disease, except for the estimated ~ 10% of familial cases in which some forty genes can be mutated with C9orf72, SOD1, TARDB, and FUS being the most common.

Pathological hallmarks of FXTAS and ALS are intracellular inclusions composed of various RNA-binding proteins and of different RNAs. I will discuss interaction of FMRP with brain cytoplasmic non-coding RNA bc1, explain the evolutionary relationship between bc1 and transfer RNAs, and present results of a biochemical study on interaction of TARDB protein TDP-43 with transfer RNAs. Protein modifications arginylation and cis to trans prolyl-peptide bond isomerization, and tRNA methylation and wybutosinylation will be discussed in the context of human neuromuscular diseases and possible diagnostic and therapeutic applications.

Several proteins involved in neuromuscular degenerations specifically recognize guanine-rich RNA structures named G-quadruplexes, and I will present a model study on the effect of benzothiazole derivatives on in vitro stability of artificial RNA G-quadruplexes.