Bita Zamiri - ۱۴۴ College Street, Leslie Dan faculty of Pharmacy, University of Toronto, Toronto Institute of Biochemistry and Biophysics, University of Tehran, Tehran

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are diseases that form a spectrum of neurodegenerative disorders. Back in 2011, it was shown that expansion of (GGGGCC)n•(GGCCCC)n in the C9orf72 gene is the main cause of ALS/FTD. Being G-rich on one strand, and C-rich on the other strand, the C9orf72 repeats would appear to have a large propensity to form secondary structures. It has been shown that different repeats of the G-rich DNA and RNA, can form G-quadruplexes- also known as four-stranded DNA or RNA- in-vitro. To date, the exact mechanism leading to pathogenesis is still not known. However, the two major theories regarding pathogenesis are loss-of-function or gain-of-function mechanisms. Supporting the gain-of-function mechanism for pathogenesis, multiple proteins have been shown to bind the C9orf72 repeat. Interestingly, some of these proteins were shown to have structure-specific binding to the higher-order structures mentioned above. Structure-specific protein binding has previously been reported for other repeat expansion diseases as well. Our studies have focused on the biophysical characterization of the structure of the G-rich and C-rich strands of the C9orf72 repeat and their binding with biologically relevant proteins and small molecules by using CD spectroscopy, UV spectroscopy and gel electrophoresis. Non-canonical structures may be important intermediates in mutagenesis; therefore, it is important to assess the relative stability of these structures and their binding to biologically relevant molecules.

C9orf72, G-quadruplexes, i-Motifs, Structure-specific protein binding