Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

BACKGROUND

Transactive response DNA-binding protein of 43 kDa (TDP-43) is an essential regulator of RNA metabolism, playing a pivotal role in splicing, transport, and stability. While its cytoplasmic aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), recent evidence suggests that the earliest pathogenic event is the disruption of its physiological homodimeric structure. Under healthy conditions, TDP-43 forms dimers via its N-terminal domain, a configuration that is crucial for its nuclear solubility and cooperative RNA binding. In this review, we propose the "Molecular Zipper" hypothesis to describe the maintenance of TDP-43 structural homeostasis. In this framework, the N-terminal domain acts as a stabilizing "NTD-mediated anchor" that keeps the protein in a functional, "zipped" dimeric state, effectively sequestering its aggregation-prone C-terminal regions. Pathogenic triggers-including genetic mutations, aberrant post-translational modifications such as phosphorylation and acetylation, and environmental stressors-can "unzip" this structure, leading to the formation of pathogenic monomers. These pathogenic monomers show increased propensity for cytoplasmic mislocalization and recruit wild-type protein into aggregates through a prion-like seeded aggregation mechanism, culminating in nuclear functional loss and cytoplasmic gain-of-toxicity. We further evaluate the emerging diagnostic landscape, focusing on methods to monitor the dimer-to-monomer ratio.

SHORT

CONCLUSION

Integrating prior biochemical data on TDP-43 dimerization with structural modeling enables a more coherent account of the transition from the physiological dimer to pathological conformers. The Molecular Zipper framework offers a conceptual foundation for reconciling existing experimental findings and for guiding future studies on early structural changes in TDP-43 proteinopathy.