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Isolating Potentiated Hsp104 Variants Using Yeast Proteinopathy Models
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Tuning Hsp104 specificity to selectively detoxify α-synuclein.

Korrie L Mack1, Hanna Kim2, Edward M Barbieri3

  • 1Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

Molecular Cell
|August 25, 2023
PubMed
Summary
This summary is machine-generated.

Researchers engineered specific Hsp104 protein variants to target toxic alpha-synuclein aggregates. These variants effectively reduce Parkinson's disease pathology in model organisms, offering a promising therapeutic strategy for neurodegenerative disorders.

Keywords:
Hsp104Parkinson’s diseasealpha-synucleindisaggregaseneurodegenerationprotein engineering

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Area of Science:

  • Biochemistry
  • Neuroscience
  • Protein aggregation

Background:

  • Heat shock protein 104 (Hsp104) is a protein disaggregase that resolves protein aggregates.
  • Misfolded proteins like alpha-synuclein, TDP-43, and FUS are implicated in neurodegenerative diseases.
  • Existing Hsp104 variants, while potent, lack substrate specificity, leading to off-target effects.

Purpose of the Study:

  • To engineer substrate-specific Hsp104 variants to reduce off-target effects.
  • To develop Hsp104 variants that selectively target alpha-synuclein toxicity.

Main Methods:

  • Altering Hsp104 pore loops to change substrate engagement.
  • Testing variant specificity against alpha-synuclein, TDP-43, and FUS toxicity.
  • Evaluating efficacy in a C. elegans model of Parkinson's disease.

Main Results:

  • Engineered Hsp104 variants selectively suppressed alpha-synuclein toxicity without affecting TDP-43 or FUS.
  • Identified variants mitigating alpha-synuclein toxicity through disaggregation or detoxification of soluble conformers.
  • Alpha-synuclein-specific variants demonstrated superior reduction of dopaminergic neurodegeneration in vivo compared to non-specific variants.

Conclusions:

  • Increasing substrate specificity of Hsp104 variants can mitigate off-target effects.
  • Tailored Hsp104 disaggregases show potential as therapeutics for specific neurodegenerative diseases.
  • This approach could be broadly applied to develop targeted treatments for protein misfolding disorders.