A Chemical Chaperone Decouples TDP-43 Disordered Domain Phase Separation from Fibrillation

Choi, Kyoung‐Jae; Tsoi, Phoebe S.; Moosa, Mahdi Muhammad; Paulucci-Holthauzen, Adriana; Liao, Shih-Chu Jeff; Ferreon, Josephine C.; Ferreon, Allan Chris M.

doi:10.1021/acs.biochem.8b01051

Cited by 46 publications

(44 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These types of interactions could be involved in the observed early changes in material properties of droplets during the lag phase of amyloid aggregation and would therefore be optimal for therapeutic intervention. Indeed, a chemical chaperone has recently been shown to promote LLPS of TDP-43 while abrogating amyloid formation, although aggregation within the context of liquid droplets was not directly examined in this study (66). Even though further studies are needed to fully understand the link between LLPS and TDP-43 aggregation in vivo, our findings ultimately posit that LLPS is a viable, biologically relevant mechanism under which the formation of amyloid aggregates by TDP-43 may occur and contribute to the pathogenicity of neurodegenerative disorders.…”

Section: Phase Separation Promotes Aggregation Of Tdp-43mentioning

confidence: 99%

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

257

287

View full text Add to dashboard Cite

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.

show abstract

Section: Phase Separation Promotes Aggregation Of Tdp-43mentioning

confidence: 99%

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

257

287

View full text Add to dashboard Cite

show abstract

“…In cases where the structure of the natural denatured region plays an important role as a stabilizing factor for liquid droplets, the addition of osmolytes results in the dissolution of the liquid droplets in a similar way to sugars. TMAO stabilizes the liquid droplets of an intrinsically disordered protein of TDP-43, which prevents amyloid fibrilization (Choi et al 2018). By contrast, TMAO promotes the amyloid formation of tau protein (Scaramozzino et al 2006).…”

Section: Effects Of Additives On the Solution States Of Proteinsmentioning

confidence: 99%

Effect of additives on liquid droplets and aggregates of proteins

et al. 2020

View full text Add to dashboard Cite

This review briefly summarizes the effect of additives on the formation of liquid droplets and aggregates of proteins. Proteins have the property of forming liquid droplets and aggregates both in vivo and in vitro. The liquid droplets of proteins are mainly stabilized by electrostatic and cation-π interactions, whereas the amorphous aggregates are mainly stabilized by hydrophobic interactions. Crowders usually stabilize liquid droplets, whereas ions and hexandiols destabilize the droplets. Additives such as kosmotropes, sugars, osmolytes, and crowders promote the formation of amorphous aggregates, whereas additives such as arginine and chaotropes can prevent the formation of amorphous aggregates. Further, amyloid has a different mechanism for its formation from amorphous aggregates because it is primarily stabilized by a cross-β structure. These systematic analyses of additives will provide clues to controlling protein aggregations and will aid the true understanding of the transition of proteins from liquid droplets and aggregates.

show abstract

“…As a result, there is rapidly emerging interest in identifying small molecules that could regulate MLOs. Efforts in this regard have focused on molecules that disrupt LLPS 28 , 29 , though a chemical chaperone has been shown to promote LLPS at very high (0.5−2 M) concentrations 30 . However, there is growing evidence that MLOs can also be beneficial to normal functioning of the cell 4 , 31 , 32 .…”

Section: Introductionmentioning

confidence: 99%

Small molecules as potent biphasic modulators of protein liquid-liquid phase separation

et al. 2020

View full text Add to dashboard Cite

Liquid-liquid phase separation (LLPS) of proteins that leads to formation of membrane-less organelles is critical to many biochemical processes in the cell. However, dysregulated LLPS can also facilitate aberrant phase transitions and lead to protein aggregation and disease. Accordingly, there is great interest in identifying small molecules that modulate LLPS. Here, we demonstrate that 4,4’-dianilino-1,1’-binaphthyl-5,5’-disulfonic acid (bis-ANS) and similar compounds are potent biphasic modulators of protein LLPS. Depending on context, bis-ANS can both induce LLPS de novo as well as prevent formation of homotypic liquid droplets. Our study also reveals the mechanisms by which bis-ANS and related compounds modulate LLPS and identify key chemical features of small molecules required for this activity. These findings may provide a foundation for the rational design of small molecule modulators of LLPS with therapeutic value.

show abstract

A Chemical Chaperone Decouples TDP-43 Disordered Domain Phase Separation from Fibrillation

Cited by 46 publications

References 29 publications

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

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

Effect of additives on liquid droplets and aggregates of proteins

Small molecules as potent biphasic modulators of protein liquid-liquid phase separation

Contact Info

Product

Resources

About