Delineating the membrane-disrupting and seeding properties of the TDP-43 amyloidogenic core

Liu, Gerard Chun-Hao; Chen, Bryan Po-Wen; Ye, Nancy Ting-Juan; Wang, Chih‐Hsien; Chen, Wenlung; Lee, Hsien-Ming; Chan, Sunney I.; Huang, Joseph Jen‐Tse

doi:10.1039/c3cc46762g

Cited by 31 publications

(35 citation statements)

References 21 publications

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“…Since it has been shown that the addition of proline residues may block β-sheet propensity and prevent amyloidogenesis, various glycines were replaced by prolines in TDP-43 glycine-rich peptides (G294P, GGG294PPP, and GGG308PPP) to confirm the impact of proline substitutions in the peptide aggregation and cytotoxicity. While GGG294PPP was selected due to the frequent pathological mutations in residues 294 and 295, GGG308PPP was chosen for the amyloidogenic property in the specific region (residue 307–322) of TDP-43 [19]. Our result indicated the impact of pathological and de novo designed mutations in the amyloid formation and shed light on the possible peptide design in suppressing TDP-43 proteinopathy in the future.…”

Section: Introductionmentioning

confidence: 82%

The Influence of Pathological Mutations and Proline Substitutions in TDP-43 Glycine-Rich Peptides on Its Amyloid Properties and Cellular Toxicity

et al. 2014

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TAR DNA-binding protein (TDP-43) was identified as the major ubiquitinated component deposited in the inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in 2006. Later on, numerous ALS-related mutations were found in either the glycine or glutamine/asparagine-rich region on the TDP-43 C-terminus, which hinted on the importance of mutations on the disease pathogenesis. However, how the structural conversion was influenced by the mutations and the biological significance of these peptides remains unclear. In this work, various peptides bearing pathogenic or de novo designed mutations were synthesized and displayed their ability to form twisted amyloid fibers, cause liposome leakage, and mediate cellular toxicity as confirmed by transmission electron microscopy (TEM), circular dichroism (CD), Thioflavin T (ThT) assay, Raman spectroscopy, calcein leakage assay, and cell viability assay. We have also shown that replacing glycines with prolines, known to obstruct β-sheet formation, at the different positions in these peptides may influence the amyloidogenesis process and neurotoxicity. In these cases, GGG308PPP mutant was not able to form beta-amyloid, cause liposome leakage, nor jeopardized cell survival, which hinted on the importance of the glycines (308–310) during amyloidogenesis.

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Section: Introductionmentioning

confidence: 82%

The Influence of Pathological Mutations and Proline Substitutions in TDP-43 Glycine-Rich Peptides on Its Amyloid Properties and Cellular Toxicity

et al. 2014

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“…The aggregation propensity of TDP‐43 may be dependent on the region of the C‐terminal altered as the core aggregation sequences are in specific locations of the C‐terminus [165]. Using a number of recombinant TDP‐43 CTF peptides of the core aggregation sequence, one group were able to induce the formation of TDP‐43‐positive amyloid fibrils and seeding reactions in vitro and cell culture [166]. However, truncation beyond residues 317 were not able to induce amyloid fibrils and formed amorphous aggregates [166].…”

Section: Introductionmentioning

confidence: 99%

“…Using a number of recombinant TDP‐43 CTF peptides of the core aggregation sequence, one group were able to induce the formation of TDP‐43‐positive amyloid fibrils and seeding reactions in vitro and cell culture [166]. However, truncation beyond residues 317 were not able to induce amyloid fibrils and formed amorphous aggregates [166]. Therefore, residue‐specific post‐translational modifications to this region may be the pathogenic event leading to a pathological TDP‐43 amyloid formation and templated seeding reaction.…”

Section: Introductionmentioning

confidence: 99%

Review: Prion‐like mechanisms of transactive response DNA binding protein of 43 kDa (TDP‐43) in amyotrophic lateral sclerosis (ALS)

Smethurst

Sidle

Hardy

2015

Neuropathology Appl Neurobio

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Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder which predominantly affects the motor neurons in the brain and spinal cord. The death of the motor neurons in ALS causes subsequent muscle atrophy, paralysis and eventual death. Clinical and biological evidence now demonstrates that ALS has many similarities to prion disease in terms of disease onset, phenotype variability and progressive spread. The pathognomonic ubiquitinated inclusions deposited in the neurons and glial cells in brains and spinal cords of patients with ALS and fronto-temporal lobar degeneration with ubiquitinated inclusions contain aggregated transactive response DNA binding protein of 43 kDa (TDP-43), and evidence now suggests that TDP-43 has cellular prion-like properties. The cellular mechanisms of prion protein misfolding and aggregation are thought to be responsible for the characteristics of prion disease. Therefore, there is a strong mechanistic basis for a prion-like behaviour of the TDP-43 protein being responsible for some characteristics of ALS. In this review, we compare the prion-like mechanisms of TDP-43 to the clinical and biological nature of ALS in order to investigate how this protein could be responsible for some of the characteristic properties of the disease.

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“…Even though the specific nature of TDP-43 aggregates from patient histopathological samples is a topic for discussion (1, 18 -20), the prion-like progressive behavior of TDP-43 proteinopathies (21)(22)(23)(24) suggests that these aggregates have a seeding capacity characteristic of amyloids. Consistent with this notion, recent studies have revealed that the isolated LCD (13) and many of its fragments (25)(26)(27)(28)(29)(30)(31) readily form amyloid fibrils, whereas deletion of or within this region abrogates fibrillation (32)(33)(34). However, little is known about the mechanism of this amyloidogenic pathway.…”

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confidence: 97%

The role of liquid–liquid phase separation in aggregation of the TDP-43 low-complexity domain

Babinchak

Raza

Dumm

et al. 2019

Journal of Biological Chemistry

303

287

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Pathological aggregation of the transactive response DNAbinding protein of 43 kDa (TDP-43) is associated with several neurodegenerative disorders, including ALS, frontotemporal dementia, chronic traumatic encephalopathy, and Alzheimer's disease. TDP-43 aggregation appears to be largely driven by its low-complexity domain (LCD), which also has a high propensity to undergo liquid-liquid phase separation (LLPS). However, the mechanism of TDP-43 LCD pathological aggregation and, most importantly, the relationship between the aggregation process and LLPS remains largely unknown. Here, we show that amyloid formation by the LCD is controlled by electrostatic repulsion. We also demonstrate that the liquid droplet environment strongly accelerates LCD fibrillation and that its aggregation under LLPS conditions involves several distinct events, culminating in rapid assembly of fibrillar aggregates that emanate from within mature liquid droplets. These combined results strongly suggest that LLPS may play a major role in pathological TDP-43 aggregation, contributing to pathogenesis in neurodegenerative diseases.

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Delineating the membrane-disrupting and seeding properties of the TDP-43 amyloidogenic core

Cited by 31 publications

References 21 publications

The Influence of Pathological Mutations and Proline Substitutions in TDP-43 Glycine-Rich Peptides on Its Amyloid Properties and Cellular Toxicity

The Influence of Pathological Mutations and Proline Substitutions in TDP-43 Glycine-Rich Peptides on Its Amyloid Properties and Cellular Toxicity

Review: Prion‐like mechanisms of transactive response DNA binding protein of 43 kDa (TDP‐43) in amyotrophic lateral sclerosis (ALS)

The role of liquid–liquid phase separation in aggregation of the TDP-43 low-complexity domain

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