Using iPSCs to delineate the roles of midbrain dopaminergic neurons and astrocytes in Parkinson's disease

Parkinson's disease (PD) is an age-related neurodegenerative disorder that remains incurable. It is primarily characterised by the degeneration of midbrain dopaminergic neurons in the substantia nigra. Loss of dopaminergic neurons affects the motor system, leading to ridigity and tremor phenotypes (Kalia and Lang 2015). As the disease progresses, degeneration of cortical neurons follows, which results in dementia and psychiatric problems. At a cellular level, insoluble aggregated forms of the protein alpha-synuclein are very common in sporadic PD and are usually deposited in lewy bodies (Choi and Gandhi 2018). Indeed, there are no true disease modifying therapies, likely secondary to our lack of understanding of the underlying molecular pathogenesis of the human disease.

The development of induced pluripotent stem cells (iPSCs) has provided us with the potential to study the development of PD in a more relevant human cellular model. Using iPSC lines and mimicking neuronal development with morphogens allows us to develop midbrain dopaminergic neurons in vitro. However, current established protocols to differentiate control and patient specific iPSC lines result in a low efficiency of mature midbrain dopaminergic neurons (Kriks et al. 2011; Kirkeby et al. 2012). During neuronal development, gradients of morphogens activate different transcription factors in order to dictate the fate of cells, defining different regions of the brain. The substantia nigra, which contains the majority of dopaminergic neurons, develops from the midbrain. During neuronal development, the midbrain is defined by the morphogens Wnt1, FGF8 and sonic hedgehog (Shh) (Arenas et al. 2015). Carefully defined gradients of these morphogens induce the expression of key dopaminergic precursor transcription factors which leads to the development of midbrain dopaminergic neurons.