The Different Faces of the TDP-43 Low-Complexity Domain: The Formation of Liquid Droplets and Amyloid Fibrils

Chien, Hung-Ming; Lee, Chi-Chang; Huang, Joseph Jen‐Tse

doi:10.3390/ijms22158213

Cited by 12 publications

(8 citation statements)

References 137 publications

(245 reference statements)

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“…TDP‐43 aggregation is the disease‐defining pathological hallmark in > 90% of patients with amyotrophic lateral sclerosis (ALS) and ~45% of patients with frontotemporal dementia (FTD) (Gao et al , 2017 ; Prasad et al , 2019 ; Tziortzouda et al , 2021 ). However, we still have a limited understanding of the native structure of TDP‐43 inclusions and their role in disease (Gao et al , 2017 ; Chien et al , 2021 ). Predominantly, cytoplasmic neuronal inclusions of TDP‐43 correlate strongly with regional neuron loss in spinal cord, motor cortex, or frontal‐temporal cortical regions (Mackenzie et al , 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Gel‐like inclusions of C‐terminal fragments of TDP‐43 sequester stalled proteasomes in neurons

et al. 2022

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Aggregation of the multifunctional RNA-binding protein TDP-43 defines large subgroups of amyotrophic lateral sclerosis and frontotemporal dementia and correlates with neurodegeneration in both diseases. In disease, characteristic C-terminal fragments of ~25 kDa ("TDP-25") accumulate in cytoplasmic inclusions. Here, we analyze gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics, and functional assays. In neurons, cytoplasmic TDP-25 inclusions are amorphous, and photobleaching experiments reveal gel-like biophysical properties that are less dynamic than nuclear TDP-43. Compared with full-length TDP-43, the TDP-25 interactome is depleted of low-complexity domain proteins. TDP-25 inclusions are enriched in 26S proteasomes adopting exclusively substrate-processing conformations, suggesting that inclusions sequester proteasomes, which are largely stalled and no longer undergo the cyclic conformational changes required for proteolytic activity. Reporter assays confirm that TDP-25 impairs proteostasis, and this inhibitory function is enhanced by ALScausing TDP-43 mutations. These findings support a pathophysiological relevance of proteasome dysfunction in ALS/FTD.

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Section: Introductionmentioning

confidence: 99%

Gel‐like inclusions of C‐terminal fragments of TDP‐43 sequester stalled proteasomes in neurons

et al. 2022

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“…TDP-43 has been shown in vitro to undergo liquid-liquid phase separation (LLPS) due to its low complexity domain (LCD) in the C-terminal part of the protein - forming dense liquid-like membrane-less organelles termed biomolecular condensates (BMCs) (Chien et al, 2021; Molliex et al, 2015). PTMs often occur in this LCD domain and have therefore emerged as powerful modulators of LLPS and condensate formation (Hofweber and Dormann, 2019).…”

Section: Introductionmentioning

confidence: 99%

The post-translational modification SUMO affects TDP-43 phase separation, compartmentalization, and aggregation in a zebrafish model

Maurel

Scherer

Hogan

et al. 2022

Preprint

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TDP-43 is a nuclear RNA-binding protein that can undergo liquid-liquid phase separation (LLPS) and forms pathological insoluble aggregates in frontotemporal dementia and amyotrophic lateral sclerosis (ALS). Perturbations of TDP-43 function are linked to mislocalization and neurodegeneration. By studying TDP-43 in vivo, we confirmed for the first time that TDP-43 undergoes LLPS and forms biomolecular condensates in spinal motor neurons (MNs). Importantly, we discovered that interfering with the K136 SUMOylation site of TDP-43 altered its phase separation behavior, reducing cytoplasmic mislocalization and aggregation. Introduction of the ALS-linked mutation G294V did not alter these LLPS characteristics, indicating that posttranslational modifications such as lysine-specific alterations can modulate TDP-43 pathogenesis through regulating phase separation. Altogether, our in vivo characterization of TDP-43 confirms the formation of dynamic nuclear TDP-43 condensates in zebrafish spinal neurons and establishes a critical platform to validate the molecular grammar of phase separation that underpins TDP-43 aggregation in ALS and other proteinopathies.

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“…It is now widely known that it binds to UG-rich repeats of target RNAs, and it has a pivotal role in regulating mRNA transcription, splicing, transport, and stability. Under physiological conditions, TDP-43 is expressed in the nucleus and can shuttle between nucleus and cytoplasm [33]. However, under pathological conditions, it can translocate to the cytoplasm where forms amyloid fibrils and inclusion bodies leading to neuronal cell death (we suggest reading the review by Chen et al for more details [34]).…”

Section: Discussionmentioning

confidence: 99%

The Role of TAR DNA Binding Protein 43 (TDP-43) as a CandiDate Biomarker of Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

et al. 2023

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Background: TAR DNA-binding protein 43 (TDP-43) aggregation in neuronal cells is recognized as a hallmark of amyotrophic lateral sclerosis (ALS). Although the literature strongly supports the pathogenetic role of TDP-43 in ALS pathogenesis, the role of TDP-43 as a biomarker of ALS is controversial. We performed a systematic review and meta-analysis to assess the diagnostic performance of TDP-43 for ALS. Methods: Relevant publications were identified by a systematic literature search on PubMed and Web of Science from their inception to April 8, 2022. Results: Seven studies, including 472 individuals, of whom 254 had ALS according to the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, met the inclusion criteria for our meta-analysis. According to the random-effects model, CSF TDP-43 levels are higher in ALS patients compared with control groups. Conclusions: CSF TDP-43 could represent a biomarker of ALS, but further studies are mandatory before drawing conclusions.

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The Different Faces of the TDP-43 Low-Complexity Domain: The Formation of Liquid Droplets and Amyloid Fibrils

Cited by 12 publications

References 137 publications

Gel‐like inclusions of C‐terminal fragments of TDP‐43 sequester stalled proteasomes in neurons

Gel‐like inclusions of C‐terminal fragments of TDP‐43 sequester stalled proteasomes in neurons

The post-translational modification SUMO affects TDP-43 phase separation, compartmentalization, and aggregation in a zebrafish model

The Role of TAR DNA Binding Protein 43 (TDP-43) as a CandiDate Biomarker of Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

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