New Strategies of Parkinson’s Disease Treatment

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. It affects about 1% of the population over 65 worldwide. Current therapies for PD only focus on reducing motor symptoms. There are no significant neuroprotective interventions that are available to treat the disease. It is necessary to investigate the effective treatments for PD. In the past, we conducted the first clinical trial of transplantation of fetal ventral mesencephalon in an advanced PD patient in Taiwan1. We also successfully confirmed that an artificial dopaminergic neural pathway was reconstructed from substantia nigra (SN) to striatum in adult rodents2-6. We will continue our research effort in searching novel treatments for PD and organize this 3-year group proposal at Taipei Medical University with the collaboration of international neuroscientists. We will take three parallel strategies which are (1) cell therapy, (2) physical exercise and (3) new neuroprotective drugs (4) modification of apoptotic processes to develop effective therapies for PD. Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients hold great potential for the treatment of neurodegenerative disorders, as they could become an unlimited and autologous source for cell replacement therapy. To produce safe and effective cells for transplantation, we need to optimize the differentiation, isolation and post-transplantation efficacy of iPSC derived DA neurons. Our proposal aims at studying the genes and mechanisms needed to optimize DA differentiation of iPSCs, and identify factors that significantly enhance DA neuron survival and integration after transplantation. Specifically in vivo fluorescent markers will be used to determine the efficiency of differentiation, composition of the grafts, survival rates after transplantation, and the degree of integration with the surrounding host tissue. Recent studies demonstrate that physical exercise can reduce the behavioral and neuropathological effects of toxins directed toward those neurons largely responsible for the motor deficits of PD, the DA neurons of the SN; clinical studies are consistent with these findings. However, the mechanisms underlying exercise-induced neuroprotection have not been elucidated and may include new therapeutic targets. Moreover, such studies provide correlations, rather than significant insight into the causal sequences linking exercise to neuroprotection. Our studies are to determine how exercise protects DA function and, thus, to provide an understanding of exercise-induced neuroprotection to guide development of novel effective therapies. Previous studies have demonstrated that pretreatment with the endogenous incretin, glucagon-like peptide-1 (GLP-1) may provide neurotrophic and neuroprotective actions in many acute and chronic neurodegenerative animal models either in vitro or in vivo, including PD models, via GLP-1 receptor stimulation. However, the effect of glucose-dependent insulinotropic polypeptide (GIP), another important incretin similar to GLP-1 with respect to insulin stimulation, on neuronal systems is still unclear. The objective of this project is to study over three years clinical relevance of the neurotrophic and neuroprotective capacities of GIP not only in PD patients but also in those who may suffer from both diabetes mellitus and PD. During the past decade, neural transplantation has been shown to be a potential therapeutic strategy for neurodegenerative disease. However, one of the major challenges in cell replacement therapy in neurodegenerative disease is the low survival rate of transplanted cells. Here, we hypothesize that p53 is involved both in the cell death associated with transplantation and pathological processes in neurodegenerative disease. We propose that inactivation or inhibition of p53 function will protect the targeted cells in both transplantation procedures and in pathological processes in animal models of neurodegenerative disease. We will test this hypothesis in a combined genetic and pharmacological approach in an animal model of PD. We believe the results generated through this group proposal will significantly advance the development of highly effective therapeutic methods for treating neurodegenerative disorders.