Recent advances in cellular models for discovering prion disease therapeutics

ABSTRACT

Introduction

Prion diseases are a group of rare and lethal, rapidly progressive neurodegenerative diseases arising due to conversion of the physiological cellular prion protein into its pathological counterparts, denoted as ‘prions.’ These agents are resistant to inactivation by standard decontamination procedures and can be transmitted between individuals, consequently driving the irreversible brain damage typical of the diseases.

Areas covered

Since its infancy, prion research has mainly depended on animal models for untangling the pathogenesis of the disease as well as for the drug development studies. With the advent of prion-infected cell lines, relevant animal models have been complemented by a variety of cell-based models presenting a much faster, ethically acceptable alternative.

Expert Opinion

To date, there are still either no effective prophylactic regimens or therapies for human prion diseases. Therefore, there is an urgent need for more relevant cellular models that best approximate in vivo models. Each cellular model presented and discussed in detail in this review has its own benefits and limitations. Once embarking in a drug screening campaign for the identification of molecules that could interfere with prion conversion and replication, one should carefully consider the ideal cellular model.

KEYWORDS:

• 2D cellular models
• 3D cell-based models
• drug screening
• mammalian prions
• prion diseases
• prion strains
• yeast prions

Article highlights

• Prion diseases are a highly heterogeneous group of infective and invariably fatal diseases severely damaging the CNS of both humans and animals. A major culprit in prion diseases is a misfolded, pathological isoform of the physiological PrP^C, known as PrP^Sc. As the pathological mechanisms underlying these diseases still remain poorly understood, no effective treatments for prion diseases have been reported to date.

• Elucidation of molecular mechanisms driving the diseases, using appropriate cellular or cell-based models will, in the future, aid at uncovering effective anti-prion therapies.

• Major scientific efforts made in the past few years led to significant improvements in cellular models of prion diseases, for example, the advent of CRISPR-Cas9 gene-editing technology broadened the spectrum of prion strains that can be propagated by immortalized cell lines.

• Although less physiologically relevant, compared to mammalian cellular models, yeast-based assays are an alternative platform that had lately attracted much attention in HTS for putative anti-prion therapeutics.

• Advances have also been made in other 2D models, such as primary cell cultures and iPSC-derived astrocytes, both of which were shown to replicate human prion isolates.

• 3D models better represent the in vivo state of a diseased brain and offer yet another possibility when investigating prion disease mechanisms or testing putative anti-prion therapeutics.

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 of this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Intramural SISSA funding.