Loss of dopaminergic neurons is the principal cellular pathology underlying Parkinson's disease (PD). A fundamental but unresolved challenge is how to replenish dopaminergic neurons and restore the neurotransmitter dopamine-regulated neural circuits. Transplantation of dopaminergic neurons into the striatum can reverse behavioral deficits of PD, highlighting the therapeutic value of striatal dopamine. However, the efficacy of transplanted stem cells is limited by the survival and integration of induced neurons, as well as, the potential for tumorigenesis. The long-term goal of this proposal is to define a new regenerative strategy for neuronal induction using patient-specific endogenous glial cells. Our preliminary results show that resident glia can be in vivo reprogrammed into neuroblasts in the adult striatum. These neuroblasts proliferate and generate mature neurons when supplied with neurotrophic factors or the small chemical compounds valproic acid. Most importantly, the newly generated striatal neurons can functionally integrate into local neuronal circuits.
Three aims are proposed in this application to further analyze and optimize the in vivo reprogramming process: 1) to optimize the reprogramming process for the generation of dopaminergic neurons, 2) to functionally characterize these induced dopaminergic neurons in the adult brain, and 3) to examine translatability of induced dopaminergic neurons. The results of this work may lead to an entirely novel treatment paradigm for PD.

Public Health Relevance

Parkinson's disease causes a huge financial and emotional burden to patients and their caregivers in the US. There is currently no effective cure due to permanent loss of neurons. The proposed studies will define a potentially paradigm-shifting therapeutic strategy for PD by converting a patient's own glial cells to dopaminergic neurons in the adult brain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
Zip Code
Niu, Wenze; Zang, Tong; Wang, Lei-Lei et al. (2018) Phenotypic Reprogramming of Striatal Neurons into Dopaminergic Neuron-like Cells in the Adult Mouse Brain. Stem Cell Reports 11:1156-1170
Wang, Lei-Lei; Zhang, Chun-Li (2018) Engineering new neurons: in vivo reprogramming in mammalian brain and spinal cord. Cell Tissue Res 371:201-212
Chen, Chunhai; Zhong, Xiaoling; Smith, Derek K et al. (2017) Astrocyte-Specific Deletion of Sox2 Promotes Functional Recovery After Traumatic Brain Injury. Cereb Cortex :1-16
Tang, Yu; Liu, Meng-Lu; Zang, Tong et al. (2017) Direct Reprogramming Rather than iPSC-Based Reprogramming Maintains Aging Hallmarks in Human Motor Neurons. Front Mol Neurosci 10:359
Ahmed, Amel; Wang, Lei-Lei; Abdelmaksoud, Safaa et al. (2017) Minocycline modulates microglia polarization in ischemia-reperfusion model of retinal degeneration and induces neuroprotection. Sci Rep 7:14065
Smith, Derek K; Yang, Jianjing; Liu, Meng-Lu et al. (2016) Small Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogramming. Stem Cell Reports 7:955-969
Wang, Lei-Lei; Su, Zhida; Tai, Wenjiao et al. (2016) The p53 Pathway Controls SOX2-Mediated Reprogramming in the Adult Mouse Spinal Cord. Cell Rep 17:891-903