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Related Experiment Video

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Purification of Hsp104, a Protein Disaggregase
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Engineering therapeutic protein disaggregases.

James Shorter1

  • 1Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 jshorter@mail.med.upenn.edu.

Molecular Biology of the Cell
|June 4, 2016
PubMed
Summary

Developing potent protein disaggregases offers a promising therapeutic strategy for neurodegenerative diseases like ALS, Parkinson's, and Alzheimer's by reversing protein misfolding and aggregation.

Area of Science:

  • Neurobiology
  • Protein Biochemistry
  • Drug Discovery

Background:

  • Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD) are linked to protein misfolding and aggregation.
  • Protein disaggregases can potentially reverse these pathological processes by restoring protein structure and function.
  • Existing disaggregase systems in metazoans are often impaired in neurodegenerative conditions.

Purpose of the Study:

  • To explore the potential of protein disaggregases as therapeutic agents for neurodegenerative disorders.
  • To investigate the engineering of potentiated human protein disaggregases or small-molecule enhancers for therapeutic applications.

Main Methods:

  • Engineering potentiated variants of Hsp104 (yeast protein disaggregase) to disaggregate disease-associated proteins like TDP-43, FUS, and α-synuclein.

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  • Investigating metazoan disaggregase systems (Hsp110, Hsp70, Hsp40, HtrA1) for therapeutic potential.
  • Exploring strategies to overcome the limitations of endogenous disaggregase systems.

    • Main Results:

    • Engineered Hsp104 variants show robust disaggregation of proteins linked to ALS and PD.
    • Metazoan protein disaggregase systems, though distinct from Hsp104, are potential targets for therapeutic intervention.
    • Aging, environmental factors, and genetics can compromise endogenous disaggregase function.

    Conclusions:

    • Potentiated human protein disaggregases or small-molecule enhancers represent a promising therapeutic avenue for ALS, PD, and AD.
    • Targeting protein misfolding and aggregation through disaggregase enhancement could offer transformative treatments.
    • Further research into engineering human disaggregases is warranted for neurodegenerative disease therapy.