Self-assembly of DNA sequences GGGGCC associated with ALS and FTD diseases
Department of Complex Matter, IJS
Two severe neurological disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are associated with the presence of an increased number of d(G4C2) repeats within the C9orf72 gene. Short DNA sequences containing d(G4C2)n repeats were found to form noncanonical DNA structures, in particular G-quadruplexes. Besides this, some studies indicated also their supramolecular assembly beyond the G-quadruplexes.
To elucidate the secondary and tertiary structures formed by such DNA sequences, we performed dynamic light scattering (DLS) measurements on solutions of d(G4C2), d(G4C2)2 and d(G4C2)4 and found a profound diversity in their aggregation patterns: from relatively small G-quadruplexes in case of d(G4C2)2 to extremely long G-wires observed for d(G4C2). The formation of G-wires was studied also by atomic force microscopy (AFM) imaging of drop-cast films deposited on mica surface. Only d(G4C2) formed long nanowires (~ 100 nm) confirming its superior ability to self-assemble into extensive structures.
Our ultimate goal to visualize the folding of d(G4C2) rich regions inside the long linearized DNA plasmids containing a built-in d(G4C2)48 sequence, which mimic the repeats found in the defective genes, however, still remains a challenge.
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