Beyond TDP-43: hnRNPA1 and ANXA11 as contributors to TDP-43 proteinopathy in ALS-FTD

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia are neurodegenerative disorders characterized by a systemic collapse of cellular proteostasis, RNA processing, and long-range intracellular transport. Central to these pathologies is the misregulation of RNA-binding proteins (RBPs), particularly TDP-43, which forms a structural and biochemical nexus with other RNA-binding proteins. In this review we focus on two unexplored, yet critical, binding partners of TDP-43, hnRNPA1 and ANXA11. We highlight the role of hnRNPA1 as a coordinator of neuronal splicing networks as well as how its structural failure leads to the aberrant splicing of thousands of transcripts. We discuss how ANXA11 dysfunction contributes to axonal transport failure and nucleopathy, characterized by nuclear envelope instability and Lamin B2 mislocalization. We explore the pathological synergy between these proteins and TDP-43, which promotes heteromeric co-aggregation and the impairment of the autophagy-lysosome pathway. We examine how mutations in the low-complexity domains of these proteins disrupt liquid-liquid phase separation (LLPS), accelerating the transition from dynamic biomolecular condensates into toxic, irreversible amyloid-like aggregates. We highlight how aberrant nucleocytoplasmic trafficking acts as key contributing factor to this transition, and how advanced imaging tools, such as RNA aptamers, enable the mapping of these dynamics at the nanoscale level. Finally, we discuss emerging precision-based therapeutic strategies - including antisense oligonucleotides and small-molecule stabilizers targeting cryptic pockets - alongside the diagnostic utility of neurofilament light chain (NfL) biomarkers. By shifting from a gene-centric to a systems-level framework, this review provides a unified landscape of how nuclear RNA-processing defects and cytoplasmic-membrane trafficking failures act as interconnected, compartmentally diverse entry points into motor neuron degeneration.