Reversing deleterious protein aggregation with re-engineered protein disaggregases

Jackrel, Meredith E.; Shorter, James

doi:10.4161/cc.28709

Cited by 40 publications

(69 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously reported the isolation of a series of potentiated Hsp104 MD variants that suppress the toxicity of TDP-43, FUS, and α-syn. 9,17,21 These mutations were located in MD helix 1, the distal loop between MD helix 1 and 2, and helix 3, as well as the small domain of NBD1 (Supporting Information Table 1). 9,17,21 Using pure-protein biochemistry, we determined that these variants were all potentiated by similar mechanistic principles and were typically enhanced in a nonspecific manner, suppressing the aggregation and toxicity of TDP-43, FUS, and α-syn.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…9,17,21 These mutations were located in MD helix 1, the distal loop between MD helix 1 and 2, and helix 3, as well as the small domain of NBD1 (Supporting Information Table 1). 9,17,21 Using pure-protein biochemistry, we determined that these variants were all potentiated by similar mechanistic principles and were typically enhanced in a nonspecific manner, suppressing the aggregation and toxicity of TDP-43, FUS, and α-syn. 17 The potentiating mutations are seemingly dissimilar, and we could determine no unifying features to link them.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…4−7 Because yeasts have harnessed infectious amyloids (prions) for adaptive purposes, 8 these tight amyloid-regulatory pathways could potentially be reformulated to counter protein misfolding implicated in neurodegenerative disease in humans. 9−11 Protein misfolding is implicated in numerous neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). 12,13 In ALS, certain subsets of patients display accumulations of misfolded TDP-43 or FUS.…”

Section: −3mentioning

confidence: 99%

“…17 We are aware of no other examples in which mutation at such disparate positions to both conservative and nonconservative substitutions leads to a therapeutic gain-offunction. 9,17 It is perplexing that mutation of at least ∼14% of residues in the MD can confer this effect. However, Hsp104 autoinhibition is not relieved by simply mutating any residue.…”

Section: Hsp104mentioning

confidence: 99%

“…However, this regulation appears too tight to enable Hsp104 to antagonize the excessive aggregation and toxicity caused by the overexpression of a single protein in yeast, such as TDP-43, FUS, or α-syn. 9,17,21 It remains possible that the proteomes and environmental challenges faced by other species might have created selective pressures that enabled evolution of naturally potentiated Hsp104 variants. Thus, it will be fascinating to compare the activity of Hsp104 orthologues from different species with disparate proteomes that inhabit diverse environments.…”

Section: Hsp104mentioning

confidence: 99%

See 4 more Smart Citations

Amelioration of Alpha-Synuclein in Parkinson's Disease through potentiated protein-protein interactions

Pate¹

2016

View full text Add to dashboard Cite

Hsp104, a protein disaggregase from yeast, can be engineered and potentiated to counter TDP-43, FUS, or α-synuclein misfolding and toxicity implicated in neurodegenerative disease. Here, we reveal that extraordinarily disparate mutations potentiate Hsp104. Remarkably, diverse single missense mutations at 20 different positions interspersed throughout the middle domain (MD) and small domain of nucleotide-binding domain 1 (NBD1) confer a therapeutic gain of Hsp104 function. Moreover, potentiation emerges from deletion of MD helix 3 or 4 or via synergistic missense mutations in the MD distal loop and helix 4. We define the most critical aspect of Hsp104 potentiation as enhanced disaggregase activity in the absence of Hsp70 and Hsp40. We suggest that potentiation likely stems from a loss of a fragilely constrained autoinhibited state that enables precise spatiotemporal regulation of disaggregase activity. H sp104, a hexameric AAA+ protein from yeast, catalyzes the construction and deconstruction of yeast prions.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: −3mentioning

confidence: 99%

Section: Hsp104mentioning

confidence: 99%

Section: Hsp104mentioning

confidence: 99%

See 3 more Smart Citations

Amelioration of Alpha-Synuclein in Parkinson's Disease through potentiated protein-protein interactions

Pate¹

2016

View full text Add to dashboard Cite

show abstract

The clinical trial landscape in amyotrophic lateral sclerosis—Past, present, and future

Wobst

Mack

Brown

et al. 2020

Medicinal Research Reviews

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive loss of muscle function. It is the most common adult‐onset form of motor neuron disease, affecting about 16 000 people in the United States alone. The average survival is about 3 years. Only two interventional drugs, the antiglutamatergic small‐molecule riluzole and the more recent antioxidant edaravone, have been approved for the treatment of ALS to date. Therapeutic strategies under investigation in clinical trials cover a range of different modalities and targets, and more than 70 different drugs have been tested in the clinic to date. Here, we summarize and classify interventional therapeutic strategies based on their molecular targets and phenotypic effects. We also discuss possible reasons for the failure of clinical trials in ALS and highlight emerging preclinical strategies that could provide a breakthrough in the battle against this relentless disease.

show abstract

Drivers of Hsp104 potentiation revealed by scanning mutagenesis of the middle domain

et al. 2021

View full text Add to dashboard Cite

show abstract

Reversing deleterious protein aggregation with re-engineered protein disaggregases

Cited by 40 publications

References 43 publications

Amelioration of Alpha-Synuclein in Parkinson's Disease through potentiated protein-protein interactions

Amelioration of Alpha-Synuclein in Parkinson's Disease through potentiated protein-protein interactions

The clinical trial landscape in amyotrophic lateral sclerosis—Past, present, and future

Drivers of Hsp104 potentiation revealed by scanning mutagenesis of the middle domain

Contact Info

Product

Resources

About