Abstract
Human-induced pluripotent stem cells (hiPSCs) have revolutionized our ability to model neuropsychiatric and neurodegenerative diseases, and recent progress in the field is paving the way for improved therapeutics. In this review, we discuss major advances in generating hiPSC-derived neural cells and cutting-edge techniques that are transforming hiPSC technology, such as three-dimensional “mini-brains” and clustered, regularly interspersed short palindromic repeats (CRISPR)-Cas systems. We examine specific examples of how hiPSC-derived neural cells are being used to uncover the pathophysiology of schizophrenia and Parkinson’s disease, and consider the future of this groundbreaking research.
Highlights
Neuropsychiatric and neurodegenerative diseases are major contributors to the global burden of disease [1]
In the first report describing the generation of Human-induced pluripotent stem cells (hiPSCs) from a patient with a Leucine-Rich Repeat Kinase 2 (LRRK2) G2019S mutation, differentiated DA neurons displayed an abnormal accumulation of alpha-synuclein, altered expression patterns of genes involved in oxidative stress, and an increased susceptibility to chemical stressors [115]
The generation of sensory neurons from LRRK2 G2019S hiPSCs implicated abnormal neurite outgrowth and altered calcium responses to depolarization as pathologies driving some of the nonmotor symptoms of Parkinson’s disease (PD) [125], and these abnormalities could be alleviated with pharmacologic inhibition of LRRK2
Summary
Neuropsychiatric and neurodegenerative diseases are major contributors to the global burden of disease [1]. Animal models cannot fully address the unique and complex pathophysiology of human neuropsychiatric disease, so findings are not always transferrable to the human condition. Human postmortem studies typically represent an advanced stage of disease and can be hindered by confounding factors, such as prescription and nonprescription drug use. These approaches lack the capacity to predict patient-specific clinical outcomes to therapeutic drugs. Human-induced pluripotent stem cells (hiPSCs) are uniquely qualified to address these issues, as limitless patient-derived cells can be used to model human disease, screen drugs, and even generate tissues for transplantation. We will discuss how hiPSC technology has developed into a powerful platform for studying human neuropsychiatric diseases, focusing on schizophrenia and Parkinson’s disease (PD) as representative examples
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