BE58 - Structural Variants of G-Quadruplexes in C9ORF72 Repeat Expansions and Their Implications for Neurodegeneration
SCURS Disciplines
Biology
Document Type
General Poster
Invited Presentation Choice
Service-Learning — Oral
Abstract
Title: Structural Variants of G-Quadruplexes in C9ORF72 Repeat Expansions and Their Implications for Neurodegeneration
Context: ALS and FTD are two fatal neurodegenerative disorders, and they share both clinical and molecular features. The clinical hallmark of ALS includes the loss of upper and lower motor neurons, which results in paralysis, muscle weakness, and eventual death. FTD is characterized by early-onset atrophy of the frontal and/or temporal lobes. Approximately 15% of ALS patients exhibit symptoms of FTD, while many cases of FTD also include problems with motor neurons.
Objective and Hypothesis: The most common genetic cause of ALS and FTD is the expansion of the hexanucleotide repeat GGGGCC (G4C2) in the non-coding region of the C9ORF72 gene. This review provides a discussion on the structural diversity of parallel, antiparallel, and hybrid forms of the C9ORF72 G4s and also discusses the toxic potential of the hybrid G4-DNA and RNA.
Methods: Most of the information was compiled from PubMed and other databases, dating between 2011 and 2025. The studies were grouped according to G4 topology, hybrid formation, protein interactions, and therapeutic modulation. Various techniques discussed here included circular dichroism, NMR, crystallography, RNA foci imaging, cell and iPSC neuron assays, and interventions with small molecules or antisense.
Results or Expected Results: The study highlights the parallel, antiparallel, and hybrid structural forms that can result from C9ORF72 repeats; each variant leads to different types of cellular dysfunctions. A hybrid DNA-RNA G-quadruplex could worsen degenerative effects by forming R-loops that damage DNA and trap proteins needed for other cellular processes. Numerous studies in small molecules and antisense oligonucleotides targeting these G-quadruplexes reveal that such interventions may reduce RNA aggregate formation and increase the viability of nerve cells. These findings suggest G-quadruplex structure is a key driver of C9ORF72-related neurodegeneration and a potential therapeutic target.
Conclusion(s): The results suggest that G-quadruplexes, generated by the GGGGCC-repeat expansion in C9ORF72, mediate ALS and FTD pathogenesis through transcriptional interference, protein sequestration, and genomic instability. The structural heterogeneity of these G4s, especially the DNA—RNA hybrids, is important for their disruption of cellular homeostasis. Understanding these variants clarifies the molecular basis of C9ORF72-related neurodegeneration.
Keywords
C9ORF72, Amyotrophic Lateral Sclerosis (ALS), G-Quadruplex, Genetics, DNA
Start Date
10-4-2026 9:30 AM
Location
University Readiness Center Greatroom
End Date
10-4-2026 11:30 AM
BE58 - Structural Variants of G-Quadruplexes in C9ORF72 Repeat Expansions and Their Implications for Neurodegeneration
University Readiness Center Greatroom
Title: Structural Variants of G-Quadruplexes in C9ORF72 Repeat Expansions and Their Implications for Neurodegeneration
Context: ALS and FTD are two fatal neurodegenerative disorders, and they share both clinical and molecular features. The clinical hallmark of ALS includes the loss of upper and lower motor neurons, which results in paralysis, muscle weakness, and eventual death. FTD is characterized by early-onset atrophy of the frontal and/or temporal lobes. Approximately 15% of ALS patients exhibit symptoms of FTD, while many cases of FTD also include problems with motor neurons.
Objective and Hypothesis: The most common genetic cause of ALS and FTD is the expansion of the hexanucleotide repeat GGGGCC (G4C2) in the non-coding region of the C9ORF72 gene. This review provides a discussion on the structural diversity of parallel, antiparallel, and hybrid forms of the C9ORF72 G4s and also discusses the toxic potential of the hybrid G4-DNA and RNA.
Methods: Most of the information was compiled from PubMed and other databases, dating between 2011 and 2025. The studies were grouped according to G4 topology, hybrid formation, protein interactions, and therapeutic modulation. Various techniques discussed here included circular dichroism, NMR, crystallography, RNA foci imaging, cell and iPSC neuron assays, and interventions with small molecules or antisense.
Results or Expected Results: The study highlights the parallel, antiparallel, and hybrid structural forms that can result from C9ORF72 repeats; each variant leads to different types of cellular dysfunctions. A hybrid DNA-RNA G-quadruplex could worsen degenerative effects by forming R-loops that damage DNA and trap proteins needed for other cellular processes. Numerous studies in small molecules and antisense oligonucleotides targeting these G-quadruplexes reveal that such interventions may reduce RNA aggregate formation and increase the viability of nerve cells. These findings suggest G-quadruplex structure is a key driver of C9ORF72-related neurodegeneration and a potential therapeutic target.
Conclusion(s): The results suggest that G-quadruplexes, generated by the GGGGCC-repeat expansion in C9ORF72, mediate ALS and FTD pathogenesis through transcriptional interference, protein sequestration, and genomic instability. The structural heterogeneity of these G4s, especially the DNA—RNA hybrids, is important for their disruption of cellular homeostasis. Understanding these variants clarifies the molecular basis of C9ORF72-related neurodegeneration.