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Quantifying Subcellular Ubiquitin-proteasome Activity in the Rodent Brain
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Proteasome activity modulates amyloid toxicity.

John Galvin1, Elizabeth Curran1, Francisco Arteaga1

  • 1Department of Biological Sciences, University of Denver , Denver CO 80208, United States.

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|February 12, 2022
PubMed
Summary
This summary is machine-generated.

This study shows that producing amyloid precursor protein (APP) fragments in yeast with faulty proteasomes causes cellular damage similar to Alzheimer's disease (AD). This yeast model can help test new therapies for AD-related amyloid.

Keywords:
Alzheimer's diseaseAβC99amyloid precursor protein (APP)proteostasisyeast

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Alzheimer's disease (AD) is a leading cause of dementia, characterized by amyloid precursor protein (APP) fragment accumulation.
  • The exact role of APP fragments in AD pathogenesis is not fully understood.
  • Proteasomes are crucial for protein degradation; their dysfunction is implicated in neurodegenerative diseases.

Purpose of the Study:

  • To investigate the cellular consequences of producing the C-terminal fragment of APP (C99) in proteasome-deficient yeast.
  • To establish a yeast model that mimics neuropathological features of AD for therapeutic screening.

Main Methods:

  • Yeast strains with thermosensitive mutations in proteasome subunit genes were utilized.
  • Expression of C99, a key amyloidogenic peptide precursor, was induced in these proteasome-deficient yeast cells.
  • Phenotypic analysis included assessing protein aggregates, cellular stress markers, and apoptosis.

Main Results:

  • Inducing C99 expression in proteasome-deficient yeast led to increased protein aggregates and cellular stress.
  • Electron-dense accumulations were observed in the nuclear envelope/ER, alongside abnormal DNA condensation.
  • Apoptosis was induced, indicating significant cellular damage.

Conclusions:

  • The generation of C99 and associated fragments in yeast with impaired proteasomal activity recapitulates key cellular phenotypes relevant to AD neuropathology.
  • This proteasome-deficient yeast model provides a valuable platform for evaluating therapeutics targeting AD-associated amyloid and dysfunctional degradation pathways.