Proteomics applications in prion biology and structure

Abstract

Prion diseases are a heterogeneous class of fatal neurodegenerative disorders associated with misfolding of host cellular prion protein (PrP^C) into a pathological isoform, termed PrP^Sc. Prion diseases affect various mammals, including humans, and effective treatments are not available. Prion diseases are distinguished from other protein misfolding disorders – such as Alzheimer’s or Parkinson’s disease – in that they are infectious. Prion diseases occur sporadically without any known exposure to infected material, and hereditary cases resulting from rare mutations in the prion protein have also been documented. The mechanistic underpinnings of prion and other neurodegenerative disorders remain poorly understood. Various proteomics techniques have been instrumental in early PrP^Sc detection, biomarker discovery, elucidation of PrP^Sc structure and mapping of biochemical pathways affected by pathogenesis. Moving forward, proteomics approaches will likely become more integrated into the clinical and research settings for the rapid diagnosis and characterization of prion pathogenesis.

Keywords:

• cerebrospinal fluid
• Creutzfeld–Jakob disease
• mass spectrometry
• prion diagnostics
• prion disease
• prion structure
• proteomics
• quaking-induced conversion

Acknowledgements

The authors acknowledge AC Gill, for providing feedback on portions of the draft manuscript and R Kissinger and A Mora (both from NIH/NIAID), for technical assistance with the figures.

Financial & competing interests disclosure

The authors are employees of the US NIH/NIAID and this work was funded by the Intramural Research Program at the NIH/NIAID. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• New in vitro assays have led to a significant increase in the sensitivity and specificity of PrP^Sc detection and prion disease diagnosis.

• Targeted mass spectrometry offers a key quantitative advantage in prion detection due to its ability to determine the concentration of a PrP peptide in a sample.

• Targeted mass spectrometry approaches have the potential to provide a molecular signature for prion diseases via the quantitation of multiple biomarkers simultaneously.

• Proteomics analysis of enriched PrP^Sc can be used to study the molecular basis of prion strains and identify proteins which co-purify with PrP^Sc.

• Mass spectrometry has proven to be a fundamental tool in the elucidation of PrP^Sc structure.

• Proteomics approaches have led to new insights into the biochemical pathways altered during prion disease.