Molecular Segregation of Parkinson’s Disease by Patient-derived Neurons

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Parkinson’s disease (PD) is defined by its hallmark locomotor symptoms including tremor, rigidity, bradykinesia and postural instability, which are caused by a progressive loss of nigral dopaminergic (DA) neurons. A well-recognized categorization of Parkinson’s disease is based on whether rest tremor is present or not at disease onset. PD patients who have rest tremor at onset generally have slower progression and better prognosis than PD patients without rest tremor at onset. Our preliminary study showed that the expression of genes controlling dopamine synthesis, sequestration and degradation was significantly different between midbrain DA neurons derived from induced pluripotent stem cells (iPSC) of normal subjects vs. idiopathic PD patients. Expression of some of these genes was also significantly different between idiopathic PD patients with or without rest tremor at onset. We have developed a series of new technologies including the differentiation of iPSCs to A9 DA neurons and the direct conversion of human skin fibroblasts and urinary track cells (UTCs) to midbrain DA neurons. Using these innovative technologies, the proposal aims to identify molecular signatures that can segregate PD patients and normal subjects, and distinguish PD patients with or without rest tremor at onset. The converging development of stem cell technologies enables this project to identify molecular signatures of idiopathic Parkinson’s disease, which will significantly advance PD diagnosis, research and therapeutic development.