Stem Cell-Based Therapies for Parkinson Disease

Abstract

Parkinson disease (PD) is a neurological movement disorder resulting primarily from damage to and degeneration of the nigrostriatal dopaminergic pathway. The pathway consists of neural populations in the substantia nigra that project to the striatum of the brain where they release dopamine. Diagnosis of PD is based on the presence of impaired motor features such as asymmetric or unilateral resting tremor, bradykinesia, and rigidity. Nonmotor features including cognitive impairment, sleep disorders, and autonomic dysfunction are also present. No cure for PD has been discovered, and treatment strategies focus on symptomatic management through restoration of dopaminergic activity. However, proposed cell replacement therapies are promising because midbrain dopaminergic neurons have been shown to restore dopaminergic neurotransmission and functionally rescue the dopamine-depleted striatum. In this review, we summarize our current understanding of the molecular pathogenesis of neurodegeneration in PD and discuss the development of new therapeutic strategies that have led to the initiation of exploratory clinical trials. We focus on the applications of stem cells for the treatment of PD and discuss how stem cell research has contributed to an understanding of PD, predicted the efficacy of novel neuroprotective therapeutics, and highlighted what we believe to be the critical areas for future research.

Keywords: Parkinson disease; cell transplantation; cell-based therapy; dopamine; iPSC; stem cell.

Figure 1

Pathway of dopamine biosynthesis in dopaminergic neurons and dopamine release in the brain. (A) Enzymes for the biosynthesis of dopamine are specifically expressed in midbrain dopaminergic neurons. Tyrosine hydroxylase (TH) converts tyrosine to L-dopa, which is further converted to dopamine by aromatic L-amino acid decarboxylase. (B) Dopamine pathways in the central nervous system. VTA: ventral tegmental area.

Figure 2

Stem cell therapy for Parkinson disease. Dopaminergic progenitors could be obtained from different sources of pluripotent stem cells, which are either derived from somatic cells by epigenetic reprogramming, or from IVF-derived human embryos. HLA-matched iPSC or gene-edited hyopimmunogenic ESC/iPSC lowers the risk of graft-induced rejection. Preclinical tests in neurotoxin-induced PD models in rodents and nonhuman primates show promising therapeutic effect. IVF: in vitro fertilization; HLA: human leukocyte antigen.