The cellular prion protein and its derived fragments in human prion diseases and their role as potential biomarkers

ABSTRACT

Introduction: Human prion diseases are a heterogeneous group of incurable and debilitating conditions characterized by a progressive degeneration of the central nervous system. The conformational changes of the cellular prion protein and its formation into an abnormal isoform, spongiform degeneration, neuronal loss, and neuroinflammation are central to prion disease pathogenesis. It has been postulated that truncated variants of aggregation-prone proteins are implicated in neurodegenerative mechanisms. An increasing body of evidence indicates that proteolytic fragments and truncated variants of the prion protein are formed and accumulated in the brain of prion disease patients. These prion protein variants provide a high degree of relevance to disease pathology and diagnosis.

Areas covered: In the present review, we summarize the current knowledge on the occurrence of truncated prion protein species and their potential roles in pathophysiological states during prion diseases progression. In addition, we discuss their usability as a diagnostic biomarker in prion diseases.

Expert opinion: Either as a primary factor in the formation of prion diseases or as a consequence from neuropathological affection, abnormal prion protein variants and fragments may provide independent information about mechanisms of prion conversion, pathological states, or disease progression.

KEYWORDS:

• Human prion diseases
• sporadic Creutzfeldt-Jakob disease
• protein misfolding
• aggregation
• neurodegeneration

Article highlights

• Early and accurate diagnosis of human prion diseases is necessary to distinguish these disorders from other rapidly evolving neurodegenerative diseases

• RT-QuIC provides a milestone as a diagnostic tool for the detection of PrP^Sc in body fluids; however, this technique has limitations for early and differential prion disease diagnosis

• Low t-PrP levels can be considered as a part of the characteristic CSF profile in prion diseases

• Deposition of abnormal truncated PrP forms, beside fl-PrP^Sc, has been reported in the brain of patients afflicted with prion diseases, indicating pathophysiological relevance

• Truncated PrP species can also be found in different body fluids

• Systematic characterization of abnormal PrP variants and fragments is clearly needed to understand their role in disease mechanisms and to investigate their usage as a biomarker

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

Work of HCA is supported by the Werner-Otto-Stiftung, Hamburg, and the American CJD Foundation. The project was supported by the Alzheimer Forschung Initiative (AFI) project 17022. Spanish Ministry of Health—Instituto Carlos III [Miguel Servet programme—CP16/00041) to FL].