TDP-43 and RNA-protein interactions: Advancing understanding and diagnosis in ALS pathogenesis

The field of neurodegenerative disease research has increasingly focused on the roles of RNA-binding proteins in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A central figure in this landscape is TDP-43, a multifunctional RNA-binding protein whose perturbation has been linked to the onset and progression of ALS and FTD. While foundational studies highlighted TDP-43’s cytoplasmic mislocalization and nuclear clearance as primary pathological events, recent evidence reveals that nuclear aggregation of TDP-43 may represent an even earlier and critical trigger in disease development. Despite considerable progress in identifying the molecular functions of TDP-43 in RNA splicing, stability, and translation, the precise mechanisms by which its dysfunction leads to clinical symptoms—motor dysfunction, cognitive impairment, and behavioral changes—remain incompletely understood, with key questions surrounding the primacy of gain-of-function versus loss-of-function toxicity, the nature of pathogenic aggregates, and the variable vulnerability of neuronal populations.This Research Topic aims to advance our mechanistic understanding of TDP-43 proteinopathy across molecular, cellular, and systemic levels. The specific objectives include elucidating how aberrant RNA-protein interactions, post-translational modifications, and misregulated nucleocytoplasmic trafficking of TDP-43 lead to its aggregation and toxicity in neural cells. Further, the topic seeks to dissect the downstream effects of TDP-43 pathology, such as neuroinflammation, synaptic dysfunction, and selective neuronal loss, while also exploring the role of phase separation and prion-like domains in the formation and spread of pathology. Key questions to be addressed involve the initial triggers of TDP-43 aggregation in sporadic cases, characterization of the most neurotoxic aggregate species, and the interplay between TDP-43 and other risk proteins in ALS-FTD.This Research Topic encompasses a range of mechanistic, pathological, and translational questions in ALS-FTD, with a particular emphasis on TDP-43 proteinopathy. Although the focus is on TDP-43, contributions that address the broader context of RNA-protein dysregulation and disease-modifying interactions with other proteins are welcome. To gather further insights in TDP-43 dysfunction in ALS-FTD, we welcome articles addressing, but not limited to, the following themes:- Mechanisms of RNA-protein interactions driving TDP-43 aggregation- Post-translational modifications and nucleocytoplasmic trafficking in TDP-43 pathology- Biophysical and structural characterization of TDP-43 aggregates, including phase separation and prion-like domains- Cellular and molecular pathways linking TDP-43 pathology to neuroinflammation, synaptic dysfunction, and selective neuronal vulnerability- Diagnostic and therapeutic strategies targeting TDP-43, such as aptamer development and aggregation clearance approaches- Integration of multi-omics and advanced imaging to map TDP-43 dynamics and pathogenic progressionTopic Editor Dr. I-Fan Wang is CEO and co-founder of Garage Brain Science (GBS), a biotechnology company with activities relevant to the scope of this Research Topic. The other Topic Editors declare no competing interests with regard to the Research Topic subject. Topic editors: Elsa Zacco, I-Fan Wang, Yun Li Source: https://www.frontiersin.org/research-topics/79677/tdp-43-and-rna-protein-interactions-advancing-understanding-and-diagnosis-in-als-pathogenesis