Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that predominantly affects dopaminergic (DA) neurons of the substantia nigra. Current treatment options for PD are symptomatic and typically involve the replacement of DA neurotransmission by DA drugs, which relieve the patients of some of their motor symptoms. However, by the time of diagnosis, patients have already lost about 70% of their substantia nigra DA neurons and these drugs offer only temporary relief. Therefore, cell replacement therapy has garnered much interest as a potential treatment option for PD. Early studies using human fetal tissue for transplantation in PD patients provided proof of principle for cell replacement therapy, but they also highlighted the ethical and practical difficulties associated with using human fetal tissue as a cell source. In recent years, advancements in stem cell research have made human pluripotent stem cells (hPSCs) an attractive source of material for cell replacement therapy. Studies on how DA neurons are specified and differentiated in the developing mouse midbrain have allowed us to recapitulate many of the positional and temporal cues needed to generate DA neurons in vitro. However, little is known about the developmental programs that govern human DA neuron development. With the advent of single-cell RNA sequencing (scRNA-seq) and bioinformatics, it has become possible to analyze precious human samples with unprecedented detail and extract valuable high-quality information from large data sets. This technology has allowed the systematic classification of cell types present in the human developing midbrain along with their gene expression patterns. By studying human development in such an unbiased manner, we can begin to elucidate human DA neuron development and determine how much it differs from our knowledge of the rodent brain. Importantly, this molecular description of the function of human cells has become and will increasingly be a reference to define, evaluate, and engineer cell types for PD cell replacement therapy and disease modeling.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and its prevalence continues to increase as the population ages (Poewe et al, 2017)
Our scRNA-seq analysis and comparison of the developing human and murine ventral midbrain (VM) demonstrated that transcription factor (TF) required for midbrain dopaminergic (mDA) neuron development in mice are generally expressed in homologous mouse and human cell types (La Manno et al, 2016)
Most of our knowledge about mDA neuron development has come from studies in mice and little was known about the developmental programs that govern human mDA neuron development
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and its prevalence continues to increase as the population ages (Poewe et al, 2017). We recently used scRNA-seq to analyze and compare the human and murine VM at different stages of development, covering mDA neuron specification, neurogenesis and differentiation in both the human (weeks 6–11) and the mouse (E11.5 – E18.5) (La Manno et al, 2016).
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