Self-assembly of DNA sequences GGGGCC associated with ALS and FTD diseases

Lea Spindler
Department of Complex Matter, IJS

Abstract:

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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