Gene expression studies of the VTA in an animal model of Parkinson's disease and the emergence of gremlin as a dopaminergic neuroprotective factor
Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder afflicting as many as one million Americans and is thought to arise from a loss of dopamine (DA) signaling in the striatum due to the progressive degeneration of DA neurons of the Substantia Nigra (SN). Importantly, neighboring DA cells of the Ventral Tegmental Area (VTA) are relatively spared, raising the hypothesis that there are factors intrinsic to the VTA that are neuroprotective. The studies presented in this thesis aimed to test this hypothesis. Studies were conducted by generating an MPTP mouse model of PD, followed by genomic scale gene expression analysis of the DA neurons of the SN and VTA. Examination of the results revealed that the VTA has a dynamic transcriptional response to MPTP treatment. This response encompasses many areas of cellular function, including protein regulation, ion/metal regulation, and increased expression of peptides thought to be neuroprotective. Notably, this response was largely absent in the cells of the SN. Following gene expression analysis, we set out to develop a primary culture assay system in which to test VTA derived neuroprotective factors in the absence of VTA neurons. We were successfully able to separate SN and VTA neurons from the mouse midbrain, and culture them independent of each other, thus creating a model system in which to test VTA derived protective factors. One such factor identified as being upregulated in the VTA was gremlin. Using cell lines, primary cell culture, and a mouse model of PD, we showed that gremlin was neuroprotective against MPTP/MPP+ both in vivo and in vitro. Moreover, we demonstrated that the protective activity of gremlin was dependent on the VEGF receptor-MAP kinase signaling pathway. In conclusion, these studies provide strong evidence that the VTA has an active response to MPTP insult, including the upregulation of many potentially protective factors, such as gremlin. In the future, these studies may aid in the development of novel therapeutics for the treatment of PD and related movement disorders.
Phani, Sudarshan, "Gene expression studies of the VTA in an animal model of Parkinson's disease and the emergence of gremlin as a dopaminergic neuroprotective factor" (2011). ETD Collection for Thomas Jefferson University. AAI3449680.