This theoretical framework proposes the Zinc Finger Governor Hypothesis: TDP-43 aggregation, a hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and increasingly observed in type 2 diabetes (T2D), may serve as a downstream biomarker rather than the primary driver of pathology. Instead, it signals upstream functional impairment of metallostructural "governors"—zinc finger domain (ZFD)-containing proteins such as RGNEF (ARHGEF28), whose N-terminal ZFD stabilizes its antagonistic interaction with TDP-43 (via the NF242 fragment).The hypothesis outlines three modes of ZFD failure leading to unchaperoned TDP-43 and aggregation propensity: (1) Zinc Drought (starvation via deficiency or chelators), (2) Zinc Flood (saturation/hyper-stabilization from excess mobile zinc or hijacked responses), and (3) Broken Governor (structural damage from oxidative stress or genetic variants). This framework unifies TDP-43 proteinopathies across diseases by positing local zinc dysregulation as a common trigger, with cross-disease consilience in ALS (motor neurons/retina), FTD, T2D (pancreatic beta-cells), Alzheimer's/LATE, and others.Building on prior computational modeling (Drusen-Zinc Switch), it calls for thermodynamic auditing of ZFD-IDP interfaces (e.g., via ITC matrix experiments) to map vulnerabilities and test zinc-modulating interventions. Derived via human-in-the-loop literature-based discovery (LBD) with large language models, followed by manual refinement. Intended to generate testable hypotheses on metallobiology, zinc homeostasis, and proteinopathy in neurodegeneration and metabolic disease.Cross-references: Drusen-Zinc Switch Model (https://doi.org/10.5281/zenodo.18445089).
Joshua Dungan (Wed,) studied this question.