Exploring pre-degenerative alterations in humans using induced pluripotent stem cell-derived dopaminergic neurons

Understanding the cellular and molecular mechanisms underlying human neurological disorders is hindered by both the complexity of the disorders and the lack of suitable experimental models recapitulating key pathological features of the disease. This is a crucial issue since a limited understanding of pathogenic mechanisms precludes the development of drugs counteracting the progression of the disease. Among neurological disorders, Parkinson’s disease (PD) is likely caused by a variable combination of genetic and environmental factors leading to the progressive degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNp) (Kalia and Lang, 2015). Animal models and post-mortem studies have provided indications that multiple cellular processes may be altered in both familiar and sporadic PD pathogenesis including protein folding and aggregation, protein membrane trafficking and mitochondrial function (Kalia and Lang, 2015). However, the various genetic models of PD do not fully recapitulate the characteristics of human disease, while postmortem tissues from patients often represent the end stage of disease and may exhibit neurochemical alterations due to chronic pharmacological treatments. The possibility to reprogram human somatic cells into cells with pluripotent potential (human induced pluripotent stem cell, hiPSC) (Takahashi et al., 2007) and to differentiate hiPSC into any cell type, including neurons, thus provides an innovative approach to model neurological diseases. On this line, more information about the pathogenesis of PD has been recently provided by iPSC technology. In particular, important disease-related pathologic events such as aberrant autophagy and mitochondrial and cytoskeletal abnormalities have been described (Zhang et al., 2017), thus pointing to these models as a valuable tool for mimicking PD phenotype in vitro. More intriguingly, at present, hiPSC likely represents a unique experimental model for recognizing pre-degenerative neuronal dysfunctions that prelude the development of full-blown PD. The prerequisite for investigating pre-degenerative defects is a comprehensive elucidation of the physiological properties of hiPSC-derived DA neurons, especially focusing on the expression and function of “core” molecules playing a critical role in neuronal physiology. The iPSC technology overcomes the inability to directly examine living human neurons, thus providing a platform for investigating the properties of any proteins in their naturally occurring neuronal population. On this line, using hiPSC-derived neurons form healthy subjects, a pharmacological characterization of various ligand-and voltage-gate ion channels has been recently reported (Dage et al., 2014; Chatzidaki et al., 2015). Moreover, a physiological characterization of human midbrain DA neurons differentiated from hiPSC has been provided, showing the ability of neurons to synthetize and release DA and the capability to reuptake DA into the cells. In the same model, the electrophysiological properties of DA neurons and the neuronal mitochondrial homeostasis have been also examined (Hartfield et al., 2014).