# G-Quadruplexes Abet Neuronal Burnout in ALS and FTD

## TL;DR

G-quadruplexes and their interactions with proteins like TDP-43 and Tau may contribute to neuronal damage in ALS and FTD, offering new therapeutic insights.

## Contribution

The study reveals that TDP-43 and Tau proteins interact with G-quadruplexes and heme to detoxify reactive oxygen species, linking these interactions to neurodegeneration.

## Key findings

- TDP-43 binds to G-quadruplex and hemin complexes, potentially detoxifying superoxide.
- Tau protein can bind multiple G-quadruplexes as a folded protein, possibly preventing aggregation.
- Loss-of-function variants in ALS/FTD lead to unchecked superoxide production, causing neuronal death.

## Abstract

Expansion of d(GGGGC)n repeat in the C9ORF72 gene is causal for Amyotrophic Lateral Sclerosis (ALS) and Frontal Temporal Dementia (FTD). Proposed mechanisms include Repeat-Associated Non-AUG translation or the formation of G-quadruplexes (GQ) that disrupt translation, induce protein aggregation, sequester RNA processing factors, or alter RNA editing. Here, I show, using AlphaFold V3 (AF3) modeling, that the TAR DNA-binding protein (TDP-43) docks to a complex of GQ and hemin. TDP-43 methionines lie over hemin and likely squelch the generation of superoxide by the porphyrin-bound Fe. These TDP-43 methionines are frequently altered in ALS patients. Tau protein, a variant of which causes ALS, also binds to GQ and heme and positions methionines to detoxify peroxides. Full-length Tau, which is often considered prone to aggregation and a prion-like disease agent, can bind to an array composed of multiple GQs as a fully folded protein. In ALS and FTD, loss-of-function variants cause an uncompensated surplus of superoxide, which sparks neuronal cell death. In Alzheimer’s Disease (AD) patients, GQ and heme complexes bound by β-amyloid 42 (Aβ4) are also likely to generate superoxides. Collectively, these neuropathologies have proven difficult to treat. The current synthesis provides a framework for designing future therapeutics.