Organoid and pluripotent stem cells in Parkinson’s disease modeling: an expert view on their value to drug discovery

ABSTRACT

Introduction: Parkinson’s disease is a devastating neurodegenerative disorder preferentially involving loss of dopaminergic neurons in the substantia nigra, leading to typical motor symptoms. While there are still no therapeutics to modify disease course, recent work using induced pluripotent stem cell (iPSC) and 3D brain organoid models have provided further insight into Parkinson’s disease pathogenesis and potential therapeutic targets.

Areas covered: This review highlights the generation of iPSC neurons and neural organoids as models for studying Parkinson’s disease. It further discusses the recent work using patient-derived neurons from both familial and sporadic forms of Parkinson’s to study disease pathogenic phenotypes and pathways. It additionally provides an evaluation of iPSC neurons and organoid models for therapeutic development in Parkinson’s.

Expert opinion: The use of Parkinson’s disease patient-derived neurons and organoids provides us with the exciting opportunity to directly investigate pathogenic mechanisms and test drug compounds in human neurons. Future studies will involve generating more sophisticated models of brain organoids, studying neuronal pathways using larger patient cohorts, and routinely assessing therapeutics in these models.

KEYWORDS:

• Induced pluripotent stem cells
• organoid
• Parkinson’s disease
• therapeutics
• dopaminergic neurons
• midbrain
• neurodegeneration
• α-synuclein
• GBA

Article highlights

• iPSC-derived dopamine neurons represent an important model for studying familial and idiopathic Parkinson’s disease mechanisms.

• Parkinson’s patient-derived dopamine neurons recapitulate key pathogenic phenotypes including α-synuclein accumulation, decreased GCase activity and organelle dysfunction.

• iPSC-derived midbrain-like organoids may offer more sophisticated and physiologically relevant 3D models for studying Parkinson’s.

• iPSC-derived neurons and organoids are useful models for drug discovery, identifying therapeutic targets, and compound screening and may also be relevant for future dopamine replacement studies.

• Several studies have used iPSC-derived neurons as models for assessing the efficacy of Parkinson’s disease therapeutics.

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 manuscript was funded by the National Institutes of Health (NIH) via grant [R01 NS076054].