The dopamine system has been identified as a critical substrate of a series of human disorders, ranging from Parkinson’s Disease (PD) to schizophrenia and autisms.  While recent genetic studies have confirmed the relevant genetic risk associated to these disorders (Simón-Sánchez et al. 2009), their pathogenesis at the cellular level remains only partially understood. Based on pathology, aberrant processing of a-synuclein is thought to play role in the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB) (Vekrellis et al. 2011). One of the key questions at the core of the discovery of novel targets for pharmacologic intervention is to understand how genetic factors in dopamine neurons interact with environmental and other cellular stressors to generate cell pathology, including downstream/upstream a-synuclein processing. This situation is particularly relevant for PD, where the presence of specific risk factors at work in dopaminergic neurons has been known for years (Chung et al. 2005).

How genetic perturbations relate to the capacity of survival and regeneration of dopaminergic neurons seems associated to different interacting factors, including environmental intoxicants, cellular housekeeping mechanisms, inflammatory response and energy balance. Recent literature indicates that PD is genetically and clinically linked to the lysosomal storage disorder Gaucher disease (GD) via a genetic-determined mechanism that leads to dysfunctional glucocerebrosidase (Gcase) enzyme resulting in atypical processing of a-synuclein (Westbroek et al. 2011, Yap et al. 2011).  The fact that lysosomal dysfunction of various kinds has been repetitively shown to induce a-synuclein aggregation provides a starting point to understand dopamine neuron PD pathophysiology.

The recent publication of a protocol that convincingly describes the method to obtain dopaminergic neurons from human inducible pluripotent stem cells (iPSC) (Kirck et al. 2011) provides a unique opportunity to understand human PD pathophysiology in vitro.  Different phenotypes were described in dopaminergic neurons obtained from iPSCs of patients with genetic mutations associated with Familiar PD (PINK1 and LRRK2) when compared with the phenotype of healthy volunteers. Interestingly, they were found more vulnerable to cellular stressors than those of healthy volunteers (Guzman et al. 2010, Cooper et al. 2012). PD-relevant pathology was generated only in iPSC-derived dopaminergic neurons and not in fibroblasts, supporting the importance to generate neurons from iPSC with a specific phenotype.

In this project we propose to develop in vitro models of PD cellular pathology using human dopaminergic neurons differentiated from either iPSC of patients affected by PD or genetically-edited human embryonic pluripotent stem cells (EPSC) with the aim to explore a-synuclein pathology and then to test pharmacologic compounds.