Cell death assays for neurodegenerative disease drug discovery

ABSTRACT

Introduction: Neurodegenerative diseases affect millions of people worldwide. Neurodegeneration is gradual over time, characterized by neuronal death that causes deterioration of cognitive or motor functions, ultimately leading to the patient’s death. Currently, there are no treatments that effectively slow the progression of any neurodegenerative disease, but improved microscopy assays and models for neurodegeneration could lead the way to the discovery of disease-modifying therapeutics.

Areas covered: Herein, the authors describe cell-based assays used to discover drugs with the potential to slow neurodegeneration, and their associated disease models. They focus on microscopy technologies that can be adapted to a high-throughput screening format that both detect cell death and monitor early signs of neurodegeneration and functional changes to identify drugs that the block early stages of neurodegeneration.

Expert opinion: Many different phenotypes have been used in screens for the development of therapeutics towards neurodegenerative disease. The context of each phenotype in relation to neurodegeneration must be established to identify therapeutics likely to successfully target and treat disease. The use of improved models of neurodegeneration, statistical analyses, computational models, and improved markers of neuronal death will help in this pursuit and lead to better screening methods to identify therapeutic compounds against neurodegenerative disease.

KEYWORDS:

• Neurodegenerative disease
• neurodegenerative disease models
• 3D neurodegenerative disease models
• neuronal death
• high throughput screening
• longitudinal microscopy
• robotic microscopy
• cox proportional hazard
• single cell analysis
• organotypic slice culture

Acknowledgments

The authors acknowledge Kathryn Claiborn who provided editorial assistance, Kelley Nelson and Gayane Abramova who provided administrative assistance, and David Cahill who provided lab maintenance and organization. Nicholas Castello supplied images using EthD1 and Irina Epstein contributed slice culture images.

Article highlights

• Neurodegenerative diseases are characterized by cell death, which produces irreversible loss in brain function, and effective therapies for these diseases could be found by detecting and targeting events that lead to and directly result in cell death.

• Animal and cell models amenable to microscopy can provide a platform for resolving and screening against the cellular and molecular bases for the disease.

• Cell death and functional assays to monitor neurodegeneration can be used to screen for therapeutic compounds.

• Longitudinal live imaging provides a more dynamic description of neurodegeneration, facilitating screening of factors that drive degeneration.

• Neuronal death represents both a critical endpoint for screening assays and an important clinical correlate for human neurodegeneration that can be used to target events that precede neuronal degeneration.

• The combination of improved models, clarified understanding of the mechanisms and events that precede neuronal death, and improved computational analyses to aid cell death assays for drug discovery should lead to discovery of new therapeutic compounds for neurodegenerative disease.

This box summarizes key points contained in the article.

Declaration of interest

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.

Reviewer Disclosures

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

Additional information

Funding

This work was supported by the Taube/Koret center and grants from the National Institutes of Health (1R37NS101996, 1RF1AG058476, 1RF1AG056151, 1P01AG054407, 5U54NS091046). The Gladstone Institutes received support from a National Center for Research Resources Grant RR18928.