Mutant prion protein-mediated aggregation of normal prion protein in the endoplasmic reticulum: implications for

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Protein Misfolding Cyclic Amplification of Prions
10:12

Protein Misfolding Cyclic Amplification of Prions

Published on: November 7, 2012

Yaping Gu1, Susamma Verghese, Ravi Shankar Mishra

  • 1Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.

Journal of Neurochemistry
|December 18, 2002
PubMed

Insights

Mutant prion protein (PrPM) aggregation in familial prion disorders can cause normal prion protein (PrPC) to aggregate, even without sequence similarity. This coaggregation may contribute to neurotoxicity and disease progression.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Familial prion disorders arise from mutations in prion protein (PrP) genes.
  • The role of normal prion protein (PrPC) in the pathogenesis of familial prion disorders is not fully understood.
  • Prion plaques show varied composition, with some containing only mutant PrP (PrPM) and others both PrPC and PrPM.

Purpose of the Study:

  • To investigate whether coaggregation of PrPC with PrPM is driven by specific PrP mutations or by the cellular location of PrPM aggregation.
  • To determine if PrPC aggregation depends on sequence homology with PrPM.

Main Methods:

  • Coexpression of mutant prion protein (PrPM) and normal prion protein tagged with green fluorescent protein (PrPC-GFP) in neuroblastoma cells.
  • Generation of two PrPM variants (PrP231T, PrP217R/231T) known to aggregate spontaneously in the endoplasmic reticulum (ER).
  • Analysis of PrPC-GFP aggregation in the presence of these PrPM variants.

Main Results:

  • PrPC-GFP aggregated when coexpressed with either PrP231T or PrP217R/231T PrPM.
  • PrPC-GFP aggregation occurred irrespective of sequence homology between PrPC and the coexpressed PrPM.
  • Intracellular aggregates of PrP231T promoted the accumulation of a C-terminal PrP fragment (CtmPrP) in the ER.

Conclusions:

  • PrPC can aggregate with mutant PrPM (PrP231T, PrP217R/231T) in a cellular model of familial prion disorders, independent of sequence homology.
  • The aggregation of PrPC is likely influenced by the cellular compartment where PrPM aggregation occurs.
  • The accumulation of CtmPrP, a potentially neurotoxic transmembrane form, is linked to PrPM aggregation within the ER, impacting prion pathogenesis.

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