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4D Imaging of Protein Aggregation in Live Cells
08:59

4D Imaging of Protein Aggregation in Live Cells

Published on: April 5, 2013

Endocytosis machinery is involved in aggregation of proteins with expanded polyglutamine domains

Anatoli B Meriin1, XiaoQian Zhang, Ilya M Alexandrov

  • 1Department of Biochemistry, Boston University Medical School, Boston, Massachusetts, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|March 8, 2007
PubMed

Insights

Cellular protein aggregation, linked to disease, is influenced by the endocytic complex (EC). Late-stage EC components promote polyglutamine aggregation, while early-stage components do not, revealing a key cellular pathway.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Protein misfolding and aggregation are implicated in cellular toxicity and various pathologies.
  • Understanding the cellular mechanisms governing protein aggregation is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate the role of cellular factors, specifically the endocytic complex (EC), in protein aggregation using polyglutamine domain-containing polypeptides.
  • To determine whether different stages of EC maturation influence the aggregation process.

Main Methods:

  • Utilized model polypeptides with polyglutamine domains in both yeast and mammalian cell systems.
  • Investigated the impact of mutations affecting the endocytic vesicle formation complex in yeast.
  • Examined the localization of EC components within protein aggregates.
  • Manipulated actin polymerization dynamics and EC component levels (e.g., Arp2, N-WASP) in both cell types.

Main Results:

  • Mutations in late-stage endocytic complex (EC) components reduced polyglutamine aggregation in yeast.
  • Specific late-stage EC proteins (Sla1, Sla2, Pan1) were found within polyglutamine aggregates.
  • Inhibition of actin polymerization enhanced polyglutamine aggregation in both yeast and mammalian cells.
  • Disruption of EC scaffolding (N-WASP) suppressed aggregation, while depletion of actin mediator Arp2 enhanced it.

Conclusions:

  • The endocytic complex (EC) plays a significant role in the aggregation of cytosolic polypeptides containing polyglutamine domains.
  • Late-stage EC components and actin dynamics are critical regulators of polyglutamine aggregation.
  • Targeting EC function or actin polymerization may offer therapeutic avenues for protein aggregation disorders.

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