Novel regulators of PrP^C expression as potential therapeutic targets in prion diseases

ABSTRACT

Introduction

Prion diseases are rare and fatal neurodegenerative disorders. The key molecular event in these disorders is the misfolding of the physiological form of the cellular prion protein, PrP^C, leading to the accumulation of a pathological isoform, PrP^Sc, with unique features. Both isoforms share the same primary sequence, lacking detectable differences in posttranslational modification, a major hurdle for their biochemical or biophysical independent characterization. The mechanism underlying the conversion of PrP^C to PrP^Sc is not completely understood, so finding an effective therapy to cure prion disorders is extremely challenging.

Areas covered

This review discusses the strategies for decreasing prion replication and throws a spotlight on the relevance of PrP^C in the prion accumulation process.

Expert opinion

PrP^C is the key substrate for prion pathology; hence, the most promising therapeutic approach appears to be the targeting of PrP^C to block the production of the infectious isoform. The use of RNA interference and antisense oligonucleotide technologies may offer opportunities for treatment because of their success in clinical trials for other neurodegenerative diseases.

KEYWORDS:

• Prion diseases
• PrP^C
• therapy
• antisense strategy

Article highlights

• Prion diseases are fatal neurodegenerative disorders with no available treatments.

• The mechanisms underlying prion infection reside in the conversion and replication of the pathological isoform, the prion, from the physiological prion protein.

• PrP^C and PrP^Sc share the same aminoacidic sequence; thus, the targeting of one of them is very challenging.

• Many therapeutic strategies are focused on lowering PrP expression because PrP^C is the only known molecule necessary for sustaining prion infection.

• RNA interference and antisense oligonucleotides appear to offer the best opportunities for the development of a new effective therapy.

Reviewer disclosures

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

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.

Additional information

Funding

This paper was not funded.