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A Bystander Mechanism Explains the Specific Phenotype of a Broadly Expressed Misfolded Protein

Lauren Klabonski1, Ji Zha1, Lakshana Senthilkumar1

  • 1Biology Department, Drexel University, Philadelphia, Pennsylvania, United States of America.

Plos Genetics
|December 8, 2016
PubMed

Insights

Misfolded proteins can damage unrelated proteins, causing disease. In C. elegans, a mutant IGF-like protein (DAF-28) disrupts TGF-β protein (DAF-7) biogenesis, leading to specific neuronal dysfunction and developmental defects.

Area of Science:

  • Cellular biology
  • Neuroscience
  • Protein misfolding diseases

Background:

  • Conformational diseases involve misfolded proteins that disrupt cellular proteostasis.
  • The 'bystander' mechanism describes collateral damage to unrelated proteins by misfolded proteins.
  • Understanding how misfolded proteins cause cell-type-specific phenotypes remains a challenge.

Purpose of the Study:

  • To investigate the gain-of-function mechanism of a folding mutation in the C. elegans IGF-like protein DAF-28.
  • To elucidate how broadly expressed mutant proteins cause cell type-selective phenotypes.
  • To identify the specific cellular targets affected by the DAF-28(R37C) mutation.

Main Methods:

  • Utilized a transgenic C. elegans model with a R37C folding mutation in the endogenous DAF-28 gene.
  • Employed functional, fluorescently-tagged proteins to track protein localization and accumulation.
  • Analyzed the impact of the mutation on the biogenesis of unrelated endogenous proteins, specifically DAF-7/TGF-β.
  • Investigated the role of unfolded protein response (UPR) pathways in modulating the observed phenotypes.

Main Results:

  • The DAF-28(R37C) mutation, though broadly expressed, selectively impairs function in the ASI neuron, causing a distinct developmental phenotype.
  • This phenotype results from the disruption of normal biogenesis of the unrelated DAF-7/TGF-β protein.
  • Wild-type DAF-7/TGF-β mislocalizes and accumulates in the proximal axon of ASI neurons in DAF-28(R37C) animals.
  • Activation of UPR branches modulates the phenotype and DAF-7 mislocalization via divergent mechanisms.

Conclusions:

  • The bystander targeting of DAF-7/TGF-β by misfolded DAF-28/IGF explains the ASI neuron-specific gain-of-function phenotype.
  • This finding suggests that bystander misfolding mechanisms may dictate distinct disease phenotypes associated with different folding mutations in conformational diseases.
  • The study highlights the complexity of proteostasis disruption and cell-type specificity in protein misfolding disorders.

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