G-Quadruplexes Abet Neuronal Burnout in ALS and FTD.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Expansion of the d(GGGGC)n repeat in the C9ORF72 gene is a known cause of Amyotrophic Lateral Sclerosis (ALS) and Frontal Temporal Dementia (FTD).
• Proposed pathogenic mechanisms include Repeat-Associated Non-AUG translation and G-quadruplex (GQ) formation, which can disrupt cellular processes.
• These GQs may interfere with translation, promote protein aggregation, sequester RNA-binding proteins, and alter RNA editing.

Purpose of the Study:

• To investigate the molecular interactions between TDP-43, Tau, G-quadruplexes (GQ), and heme in the context of neurodegenerative diseases.
• To elucidate the role of these interactions in the generation of reactive oxygen species and neuronal cell death.
• To provide a framework for developing novel therapeutic strategies for ALS, FTD, and Alzheimer's Disease (AD).

Main Methods:

• Utilized AlphaFold V3 (AF3) modeling to predict protein-ligand and protein-protein interactions.
• Analyzed the structural positioning of methionine residues in TDP-43 and Tau in relation to heme and GQ complexes.
• Synthesized existing knowledge on the role of superoxide generation in neurodegeneration.

Main Results:

• AlphaFold V3 modeling revealed that TAR DNA-binding protein (TDP-43) docks to a complex of GQ and hemin.
• TDP-43 methionines are positioned over hemin, suggesting a role in squelching superoxide generation.
• Tau protein also binds GQ and heme, with methionines positioned to detoxify peroxides; full-length Tau can bind multiple GQs.
• Loss-of-function variants in ALS and FTD lead to excess superoxide, causing neuronal death.
• In AD, GQ and heme complexes bound by β-amyloid 42 (Aβ4) may also generate superoxides.

Conclusions:

• TDP-43 and Tau protein interactions with GQ-heme complexes, particularly involving methionine residues, are implicated in ALS and FTD pathogenesis through superoxide generation.
• Dysregulation of superoxide homeostasis due to C9ORF72 repeat expansion contributes to neuronal cell death in ALS and FTD.
• Similar mechanisms involving GQ, heme, and amyloid species may contribute to Alzheimer's Disease pathology.
• Understanding these molecular interactions provides a basis for designing targeted therapeutics for these challenging neurodegenerative conditions.