{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T15:47:39Z","timestamp":1778600859504,"version":"3.51.4"},"reference-count":61,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>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\u2019s Disease (AD) patients, GQ and heme complexes bound by \u03b2-amyloid 42 (A\u03b24) are also likely to generate superoxides. Collectively, these neuropathologies have proven difficult to treat. The current synthesis provides a framework for designing future therapeutics.<\/jats:p>","DOI":"10.3390\/antiox15010005","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T12:05:35Z","timestamp":1766145935000},"page":"5","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["G-Quadruplexes Abet Neuronal Burnout in ALS and FTD"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0093-1572","authenticated-orcid":false,"given":"Alan","family":"Herbert","sequence":"first","affiliation":[{"name":"Discovery, InsideOutBio, 42 8th Street, Unit 3412, Charlestown, MA 02129, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/S1474-4422(10)70195-2","article-title":"TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia","volume":"9","author":"Mackenzie","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.ncl.2015.07.001","article-title":"Familial Amyotrophic Lateral Sclerosis","volume":"33","author":"Boylan","year":"2015","journal-title":"Neurol. 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