The study investigates the molecular mechanisms underlying the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) caused by a hexanucleotide repeat expansion (HRE) in the *C9orf72* gene. The HRE, (GGGGCC)ₙ, forms DNA and RNA G-quadruplexes and promotes RNA•DNA hybrids (R-loops). These structural polymorphisms lead to the accumulation of transcripts containing the HRE region, which bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin (NCL), an essential nucleolar protein, preferentially binds to the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. The study demonstrates that the structural polymorphism of the *C9orf72* HRE at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, providing a mechanistic model for repeat-associated neurodegenerative diseases.The study investigates the molecular mechanisms underlying the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) caused by a hexanucleotide repeat expansion (HRE) in the *C9orf72* gene. The HRE, (GGGGCC)ₙ, forms DNA and RNA G-quadruplexes and promotes RNA•DNA hybrids (R-loops). These structural polymorphisms lead to the accumulation of transcripts containing the HRE region, which bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin (NCL), an essential nucleolar protein, preferentially binds to the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. The study demonstrates that the structural polymorphism of the *C9orf72* HRE at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, providing a mechanistic model for repeat-associated neurodegenerative diseases.