C-terminal peptides modelling constitutive PrPC processing demonstrate ameliorated toxicity predisposition consequent...

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Prion diseases involve the misfolding of cellular prion protein (PrPC) into β-strand-rich conformations.
• PrPC undergoes α- and β-cleavage, producing C1 and C2 C-terminal fragments, respectively.
• The direct pathogenic influence of these fragments, particularly C2, remains largely unknown.

Purpose of the Study:

• To compare the biophysical properties and neurotoxicity of recombinant human PrP fragments C1 (huPrP-(112-231)) and C2 (huPrP-(90-231)).
• To investigate the role of these fragments in prion disease pathogenesis.

Main Methods:

• Recombinant human PrP fragments huPrP-(112-231) (C1) and huPrP-(90-231) (C2) were generated.
• Biophysical properties (misfolding, thermostability) and neurotoxicity of fragment assemblies were assessed.
• Synthetic PrP peptides modeled on a Y145STOP mutant were used to corroborate findings.

Main Results:

• HuPrP-(112-231) (C1) resisted β-strand misfolding and showed no neurotoxicity in tested assemblies.
• HuPrP-(90-231) (C2) readily adopted β-strand conformations, exhibited high thermostability, and was neurotoxic.
• Soluble oligomeric β-strand-rich conformers were essential for significant neurotoxicity.

Conclusions:

• α- and β-cleavage of PrPC generate distinct C-terminal fragments (C1 and C2) with differing biophysical and biological properties.
• Fragment C1, produced by α-cleavage, appears to be averse to prion disease pathogenesis.
• Fragment C2's propensity for β-strand misfolding and neurotoxicity highlights its potential role in disease progression.