Abstract
The abnormal expansion of hexanucleotide
repeats (HRE) GGGGCC (G4C2)n in a non coding region of
the C9orf72 gene have been found to lead to cause Amyotrophic lateral sclerosis
(ALS) and Frontotemporal dementia (FTD). The transcript of (G4C2)n
HRE accumulate as nuclear RNA foci, it sequester and inactivate RNA binding
proteins. These HRE can also undergo non ATG initiated translation, as a
consequence toxic dipeptide accumulation. HRE can form complex structure like
DNA or RNA G-quadruplex and DNA-RNA hybrid, which may cause transcriptional
abortion leading to the loss of full length RNA transcripts and accumulation of
abortive RNA transcript. In this study, we reported the transition in the
configuration of (G4C2)8 from antiparalllel to
parallel configuration against heat and in the presence of two different osmolytes
(betaine and taurine). The change in the properties and configurations of (G4C2)8
were characterized by circular dichroism (CD) spectroscopy. The parallel
configurations were observed in higher concentrations of taurine against heat. Taurine
has significant role in stabilizing the structures of (G4C2)8
while there was no such stabilization was observed in the presence of betaine.
Our findings are important in order to understand the different folding of HRE
(G4C2)n and demonstrate the conformational heterogeneity
of the HRE. The presence of different osmolytes affects the unfolding and
configurations of G-quadruplex which may be further used to design small
molecules targeting neurological disorders.