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Monitoring Cell-to-cell Transmission of Prion-like Protein Aggregates in Drosophila Melanogaster
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Prion protein paralog doppel protein interacts with alpha-2-macroglobulin: a plausible mechanism for doppel-mediated

Stefano Benvegnù1, Diego Franciotta, Josh Sussman

  • 1Scuola Internazionale Superiore di Studi Avanzati-International School for Advanced Studies (SISSA-ISAS); Italian Institute of Technology, [corrected] Trieste, Italy.

Plos One
|June 19, 2009
PubMed

Insights

Doppel protein (Dpl) binding to cellular prion protein (PrP(C)) may cause neurodegeneration by displacing metalloproteinase inhibitors like alpha-2-macroglobulin (α(2)M). This suggests a novel mechanism for prion and other neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Doppel protein (Dpl) is structurally similar to the cellular prion protein (PrP(C)) but is not normally found in the central nervous system (CNS).
  • Ectopic expression of Dpl in the brain induces neurodegeneration in mouse models.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying Dpl-induced neurodegeneration.
  • To identify Dpl binding partners and their potential roles in neuroprotection or pathogenesis.

Main Methods:

  • Native isoelectric focusing and non-denaturing polyacrylamide gel electrophoresis coupled with mass spectrometry.
  • Biochemical assays including enzyme-linked immunosorbent assays (ELISA) and surface plasmon resonance (SPR).

Main Results:

  • Identified alpha-1-inhibitor-3 (α(1)I(3)) and alpha-2-macroglobulin (α(2)M) as Dpl binding partners.
  • Demonstrated high-affinity binding between PrP(C) and Dpl, but not between PrP(C) and α(1)I(3) or α(2)M.
  • Proposed a mechanism where Dpl sequesters α(2)M, reducing its neuroprotective metalloproteinase inhibitory function.

Conclusions:

  • Dpl-induced neurodegeneration may result from the withdrawal of natural metalloproteinase inhibitors like α(2)M.
  • α(2)M may be a susceptibility factor not only in Alzheimer's disease but also in prion diseases and other neurodegenerative disorders.

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