Frontiers in Aging Neuroscience · Nov 5, 2026
The TDP-43 Pathological Axis in Amyotrophic Lateral Sclerosis and Age-Related Neurodegenerative Proteinopathies: From Protein Modification to Therapeutic Targeting
By Shilin Wang, Xingxing Yuan, Guanping Liu et al.
TAR DNA-binding protein 43 (TDP-43) is one of the main pathological proteins in amyotrophic lateral sclerosis (ALS), with TDP-43-positive inclusions present in approximately 97% of ALS cases and typically accompanied by nuclear depletion and loss of function. Since its identification in 2006 as a major component of ubiquitin-positive inclusions in ALS and frontotemporal lobar degeneration, understanding of TDP-43 pathology has evolved from a simple aggregation model into a multistep pathological axis. Aberrant and context-dependent post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, SUMOylation, poly-ADP-ribosylation, oxidative modification, arginine methylation, and proteolytic cleavage, modulate TDP-43 localization, phase behavior, stress granule dynamics, aggregation, and cell-to-cell propagation. In parallel, nuclear TDP-43 loss disrupts RNA processing, including cryptic exon repression in transcripts such as STMN2 and UNC13A, thereby contributing to axonal and synaptic dysfunction. This mini-review integrates these interconnected mechanisms and summarizes therapeutic strategies targeting protein-modifying enzymes, aberrant phase transitions, proteostasis, pathological propagation, and downstream RNA dysfunction. We further discuss clinical translation, and the challenges of selectively correcting pathological TDP-43 states while preserving its essential physiological functions. Notably, this pathological axis framework is broadly applicable to TDP-43 proteinopathies beyond ALS, including frontotemporal dementia, limbic-predominant age-related TDP-43 encephalopathy (LATE), and TDP-43 co-pathology in Alzheimer's disease. In these age-related conditions, TDP-43 interacts with tau pathology to synergistically accelerate cognitive decline and behavioral impairment, highlighting the broader relevance of TDP-43-targeting strategies for neurocognitive aging disorders.