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Polymorphism at residue 129 modulates the conformational conversion of the D178N variant of human prion protein

Adrian C Apetri1, David L Vanik, Witold K Surewicz

  • 1Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.

Biochemistry
|November 30, 2005
PubMed

Insights

Familial prion disease mutations alter human prion protein (huPrP) biophysical properties. The D178N mutation significantly increases conversion to amyloid fibrils, with M/V polymorphism at residue 129 critically influencing this process.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Genetics

Background:

  • Transmissible spongiform encephalopathies (TSEs) are linked to prion protein (PrP) mutations.
  • The PRNP gene harbors mutations causing inherited prion diseases, such as fatal familial insomnia and familial Creutzfeldt-Jakob disease.
  • The Asp178Asn (D178N) mutation in PRNP is associated with distinct phenotypes based on methionine (Met) or valine (Val) at codon 129.

Purpose of the Study:

  • To investigate the biophysical properties of human prion protein (huPrP90-231) variants with the D178N mutation.
  • To determine the impact of the methionine/valine (M/V) polymorphism at codon 129 on the D178N huPrP variant's conversion propensity and amyloid formation.

Main Methods:

  • Recombinant human prion proteins (huPrP90-231) corresponding to D178N/M129 and D178N/V129 polymorphic variants were characterized.
  • Biophysical properties, including conversion to beta-sheet-rich oligomers and amyloid fibrils, were assessed at acidic and neutral pH.
  • Thioflavine T fluorescence was used to detect amyloid fibril formation.
  • Secondary structures of wild-type and variant amyloid fibrils were analyzed.

Main Results:

  • Both D178N/M129 and D178N/V129 huPrP variants exhibited a significantly increased propensity for conversion to beta-sheet-rich oligomers and amyloid fibrils compared to wild-type huPrP.
  • The conversion propensity of the D178N variant was highly dependent on the M/V polymorphism at codon 129.
  • Wild-type huPrP showed no such dependence on the M/V polymorphism under identical conditions.
  • Amyloid fibrils formed by wild-type and D178N variants displayed distinct secondary structures, further modulated by the codon 129 polymorphism.

Conclusions:

  • The D178N mutation in the PRNP gene markedly enhances the propensity of huPrP to form amyloidogenic species.
  • The M/V polymorphism at codon 129 of PRNP plays a critical role in modulating the biophysical properties and conversion behavior of the D178N PrP variant.
  • These polymorphism-dependent biophysical differences provide a potential molecular basis for the distinct clinical phenotypes observed in familial prion diseases.

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