TDP‐43 Aggregation: The Healthy‐Toxic Balance of the Prion‐Like Domain
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
ABSTRACT TAR DNA‐binding protein 43 (TDP‐43) is a ubiquitously expressed RNA‐binding protein that plays essential roles in RNA metabolism, including transcription, splicing, transport, and stability. Pathological TDP‐43 aggregates have become a defining hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and a large subset of frontotemporal lobar degeneration (FTLD). In the last decade, increasing evidence has challenged the initial thought of TDP‐43 condensates as a purely pathological event, highlighting instead the physiological relevance of reversible self‐association, polymerization and liquid‐liquid phase separation (LLPS) in regulating TDP‐43 functions. In this review, we provide an integrated overview of the structural determinants governing TDP‐43 two‐faced polymerization, with a particular focus on the prion‐like domain and its parallelism with prion proteins. Indeed, while physiological assemblies support normal RNA processing, the dysregulation of LLPS by either disease‐associated mutations, altered RNA‐binding, aberrant post‐translational modifications, or proteolytic cleavage can promote the transition toward irreversible, pathogenic aggregates. Finally, we summarize strategies aimed at eliminating TDP‐43 aggregates or modulating its phase‐separation behavior. Altogether, this review frames TDP‐43 polymerization in both healthy and pathological conditions, offering a prion‐like centered view of TDP‐43 proteinopathies. TDP‐43 functi
Abstract
ABSTRACT TAR DNA‐binding protein 43 (TDP‐43) is a ubiquitously expressed RNA‐binding protein that plays essential roles in RNA metabolism, including transcription, splicing, transport, and stability. Pathological TDP‐43 aggregates have become a defining hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and a large subset of frontotemporal lobar degeneration (FTLD). In the last decade, increasing evidence has challenged the initial thought of TDP‐43 condensates as a purely pathological event, highlighting instead the physiological relevance of reversible self‐association, polymerization and liquid‐liquid phase separation (LLPS) in regulating TDP‐43 functions. In this review, we provide an integrated overview of the structural determinants governing TDP‐43 two‐faced polymerization, with a particular focus on the prion‐like domain and its parallelism with prion proteins. Indeed, while physiological assemblies support normal RNA processing, the dysregulation of LLPS by either disease‐associated mutations, altered RNA‐binding, aberrant post‐translational modifications, or proteolytic cleavage can promote the transition toward irreversible, pathogenic aggregates. Finally, we summarize strategies aimed at eliminating TDP‐43 aggregates or modulating its phase‐separation behavior. Altogether, this review frames TDP‐43 polymerization in both healthy and pathological conditions, offering a prion‐like centered view of TDP‐43 proteinopathies. TDP‐43 function relies on a delicate balance between reversible phase‐separated states and irreversible aggregation. Under physiological conditions, TDP‐43 forms dynamic droplets and oligomers that support normal cellular functions. In pathological contexts, this balance shifts toward aberrant aggregation, leading to toxic species. Therapeutic strategies aim to restore or maintain this equilibrium, preventing toxic aggregation while preserving functional assemblies. advs76119-abs-0001 graphical