Loss of TDP‐43 oligomerization or RNA binding elicits distinct aggregation patterns

Pérez‐Berlanga, Manuela; Wiersma, Vera I.; Zbinden, Aurélie; Vos, Laura De; Wagner, Ulrich; Foglieni, Chiara; Mallona, Izaskun; Betz, Katharina M.; Cléry, Antoine; Weber, Julien; Guo, Zhongning; Rigort, Ruben; Rossi, Pierre De; Manglunia, Ruchi; Tantardini, Elena; Sahadevan, Sonu; Stach, Oliver; Hruška-Plocháň, Marián; Allain, Frédéric; Paganetti, Paolo; Polymenidou, Magdalini

doi:10.15252/embj.2022111719

Cited by 28 publications

(13 citation statements)

References 102 publications

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“…Despite extensive research on the role of TDP-43 RRMs in pathological aggregation [3,9,13,14,25,34,35,42,44,45,62], achieving a comprehensive characterization of their structural dynamics in the presence and absence of nucleic acids based on available experimental approaches, has remained difficult. To address this gap, we employed an in-silico approach that utilized multi-replica, all-atom MD simulations, initiated from configurations taken from the NMR ensemble.…”

Section: Discussionmentioning

confidence: 99%

“…The N and C terminal domains of TDP-43 contribute towards the formation of the biomolecular condensates through liquid-liquid phase separation (LLPS) [16][17][18][19][20][21][22][23][24]. Recently, it was demonstrated that RNA-binding maintains the NTD oligomerization crucial for NTD-driven LLPS in the nucleus [25]. Factors such as disease-associated mutations, temperature fluctuations, and exposure to oxidative, osmotic, and chemical stressors [26,27], can impair nucleic acid binding, disrupt functional LLPS and ultimately cause mislocalization to the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

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RNA-binding tunes the conformational plasticity and intradomain stability of TDP-43 tandem RNA recognition motifs

Ozguney,

Mohanty,

Mittal

2024

Preprint

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TAR DNA binding protein 43 (TDP-43) is a nuclear RNA/DNA-binding protein with pivotal roles in RNA-related processes such as splicing, transcription, transport, and stability. The high binding affinity and specificity of TDP-43 towards its cognate RNA sequences (GU-rich) is mediated by highly conserved residues in its tandem RNA recognition motif (RRM) domains (aa:104-263). Importantly, the loss of RNA-binding to the tandem RRMs caused by physiological stressors and chemical modifications promotes cytoplasmic mislocalization and pathological aggregation of TDP-43. Despite the substantial implications of RNA in TDP-43 function and pathology, a comprehensive characterization of the effect of RNA-binding on conformational dynamics, interdomain interactions and intradomain stability of the tandem RRMs has not yet been conducted. Here, we employed all-atom molecular dynamics (MD) simulations to assess the effect of RNA-binding on the conformational landscape and intradomain stability of TDP-43 tandem RRMs. Our simulations reveal a high intrinsic conformational plasticity of the tandem RRMs in the absence of RNA which surprisingly, is accompanied by a tendency of RRM1 to adopt partially-unfolded conformations. While binding to RNA limits the overall conformational space of the tandem RRMs and promotes intradomain stability, several RRM-RNA contacts mediated by highly conserved residues are observed to be far more dynamic than previously inferred from NMR structural ensemble. Overall, our simulations reveal how RNA dynamically tunes the structural and conformational landscape of TDP-43 tandem RRMs, contributing to physiological function and mitigating pathological aggregation.SIGNIFICANCEThe cytoplasmic mislocalization and aggregation of TDP-43 due to loss of its RNA-binding capability is associated with the onset and progression of neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Due to the flexible nature of RNA and the presence of a disordered linker between RRM domains, characterizing the dynamic interactions between RRMs-RNA and/or RRM1-RRM2 by experiments alone has remained challenging. In this study, we performed all-atom simulations initiated from the NMR conformers of RNA-bound tandem RRMs of TDP-43 to investigate their underlying structural and conformational dynamics. Our findings indicate that RNA binding effectively reduces conformational heterogeneity in the tandem RRMs and acts as a protective factor for the unfolding and aggregation of RRM1. These effects are achieved through a combination of stable and dynamic protein-RNA interactions which involve highly conserved amino acids.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RNA-binding tunes the conformational plasticity and intradomain stability of TDP-43 tandem RNA recognition motifs

Ozguney,

Mohanty,

Mittal

2024

Preprint

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“…Substituting this into Eq. (10) reveals that the concentration of TDP-43 aggregates can be approximated with the following equation:…”

Section: Symbolmentioning

confidence: 99%

“…ALS is distinguished by the gradual decline of motor neurons, resulting in skeletal muscle weakness and, ultimately, fatality within a span of 3 to 5 years [5,6]. TDP-43, a nuclear, intrinsically disordered, soluble protein [7,8] with a molecular weight of 43 kDa [9], is synthesized in the cytoplasm, and in healthy neurons, it predominantly resides in the nucleus [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Simulating growth of TDP-43 cytosolic inclusion bodies in neuron soma

Kuznetsov

2023

Preprint

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This paper introduces a mathematical model for the growth of TDP-43 inclusion bodies. The model’s equations make it possible to determine numerically the concentrations of TDP-43 dimers, monomers, and aggregates. Assuming that all aggregates integrate into the inclusion bodies, the model predicts the size of TDP-43 inclusion bodies. In the scenario where protein degradation machinery is dysfunctional, resulting in infinite half-lives for TDP-43 dimers, monomers, and aggregates, an approximate solution of the model equations is derived. This solution, valid for large times, predicts that the inclusion body’s radius increases proportionally to the cube root of time. To the author’s knowledge, this study presents the first attempt to model the relationship between the size of TDP-43 inclusion bodies and time. The sensitivity analysis of the approximate solution indicates that the concentrations of TDP-43 monomers and aggregates, as well as inclusion body radii, are independent of the kinetic constants. However, the approximate solution becomes invalid for the scenario with physiologically relevant (finite) half-lives of TDP-43 dimers, monomers, and aggregates. In contrast to the situation with infinite half-lives, for various values of kinetic constants, the curves representing concentrations of monomers and aggregates, as well as the curves depicting inclusion body radii, converge to distinct constant values.

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TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: From pathomechanisms to therapeutic strategies

Ho,

Hsieh,

Tsai

2024

Ageing Research Reviews

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Loss of TDP‐43 oligomerization or RNA binding elicits distinct aggregation patterns

Cited by 28 publications

References 102 publications

RNA-binding tunes the conformational plasticity and intradomain stability of TDP-43 tandem RNA recognition motifs

RNA-binding tunes the conformational plasticity and intradomain stability of TDP-43 tandem RNA recognition motifs

Simulating growth of TDP-43 cytosolic inclusion bodies in neuron soma

TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: From pathomechanisms to therapeutic strategies

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