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Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy

Fiona M Menzies1, Raphael Hourez, Sara Imarisio

  • 1Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

Human Molecular Genetics
|September 11, 2010
PubMed

Insights

Puromycin-sensitive aminopeptidase (PSA) clears toxic protein fragments by enhancing macroautophagy. This enzyme protects against the accumulation and toxicity of misfolded proteins, including those linked to neurodegenerative diseases.

Area of Science:

  • Cellular Biology
  • Neuroscience
  • Biochemistry

Background:

  • Proteasomes and macroautophagy are key cellular mechanisms for clearing misfolded proteins.
  • Mammalian proteasomes are ineffective against polyglutamine (polyQ) sequences, leading to toxic peptide accumulation.
  • Puromycin-sensitive aminopeptidase (PSA) is the sole cytosolic enzyme capable of digesting polyQ sequences.

Purpose of the Study:

  • To investigate the protective role of Puromycin-sensitive aminopeptidase (PSA) against the accumulation of toxic polyQ fragments.
  • To determine if PSA influences the clearance of other aggregation-prone proteins.
  • To elucidate the mechanism by which PSA exerts its protective effects.

Main Methods:

  • Inhibition and overexpression of PSA in cultured cells, Drosophila, and mouse muscle models.
  • Assessment of polyQ-expanded huntingtin exon 1 aggregate content and toxicity.
  • Analysis of polyQ-expanded ataxin-3, mutant α-synuclein, and superoxide dismutase 1 levels.
  • Evaluation of macroautophagy activity via microtubule-associated protein 1 light chain 3-II (LC3-II) levels and autophagic degradation assays.

Main Results:

  • PSA inhibition or knockdown increased polyQ aggregate content and toxicity.
  • PSA overexpression reduced polyQ aggregate content and toxicity.
  • PSA inhibition elevated levels of other aggregation-prone proteins, including polyQ-expanded ataxin-3, mutant α-synuclein, and SOD1.
  • PSA overexpression enhanced macroautophagy, evidenced by increased LC3-II levels and autophagic degradation.

Conclusions:

  • Puromycin-sensitive aminopeptidase (PSA) plays a crucial role in protecting cells against proteotoxicity.
  • PSA promotes the clearance of aggregation-prone proteins by enhancing macroautophagy.
  • Targeting PSA may offer a therapeutic strategy for diseases associated with protein misfolding and aggregation.

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