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Assays for the Degradation of Misfolded Proteins in Cells
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"Trim"ming PolyQ proteins with engineered PML.

Neha Dhar1, Ammar Arsiwala1, Shruthi Murali1

  • 1School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia.

Biotechnology and Bioengineering
|November 12, 2019
PubMed
Summary
This summary is machine-generated.

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Researchers engineered a protein degradation system to target mutant ataxin1 (Atxn1 82Q) in spinocerebellar ataxia (SCA). This approach enhances the degradation of both soluble and aggregated forms, offering a potential treatment for PolyQ disorders.

Area of Science:

  • Neurodegenerative disease research
  • Molecular biology
  • Protein biochemistry

Background:

  • Protein misfolding and aggregation are hallmarks of neurodegenerative diseases like spinocerebellar ataxia (SCA).
  • Impaired protein degradation contributes to the accumulation of toxic protein species, leading to cellular dysfunction and degeneration.
  • Current strategies to clear misfolded proteins often lack specificity and efficiency.

Purpose of the Study:

  • To develop a novel strategy for enhanced intracellular degradation of mutant ataxin1 (Atxn1 82Q), a protein implicated in SCA.
  • To improve the specificity and efficiency of targeting both soluble and aggregated forms of disease-associated proteins.

Main Methods:

  • Engineering a fusion protein combining the E3 ubiquitin ligase, promyelocytic leukemia protein (PML), with single chain variable fragments (scFvs) specific for Atxn1 82Q monomers and aggregates.
Keywords:
PMLaggregatedegradationmonomerspinocerebellar ataxia

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  • Utilizing the engineered PML-scFv construct to target and enhance the degradation of Atxn1 82Q in mammalian cells.
  • Investigating the mechanism of aggregate solubilization, including the role of SUMOylation.

    • Main Results:

    • Demonstrated enhanced intracellular degradation of both soluble monomers and aggregated forms of mutant Atxn1 82Q.
    • Showed that the PML-mediated system effectively targeted and reduced intracellular levels of Atxn1 82Q.
    • Identified PML-mediated enhanced SUMOylation as a mechanism contributing to the solubilization of Atxn1 82Q aggregates.

    Conclusions:

    • The engineered PML-scFv system effectively enhances the degradation of misfolded and aggregated Atxn1 82Q.
    • This approach offers a promising strategy for reducing toxic protein accumulation in SCA and other PolyQ disorders.
    • Targeting protein degradation pathways represents a viable therapeutic avenue for neurodegenerative diseases caused by proteinopathies.