While dopamine (DA) neuron transplantation is a promising alternative therapy to the current pharmacological agents (e.g., levodopa) prescribed for individuals with Parkinson’s disease (PD), significant heterogeneity in clinical outcomes exists. Specifically, the underlying mechanisms responsible for the aberrant side effect, graft-induced dyskinesia (GID), a behavior that develops in a subpopulation of individuals who received primary DA neuron transplants, remains a mystery to be solved. In regard to this heterogeneity in cell therapy, our group previously became interested in the influence of certain genetic risk factors, hypothesizing that the common human single nucleotide polymorphism (SNP), rs6265, which is found in the gene for brain-derived neurotrophic factor (BDNF) and results in decreased BDNF release, is an unrecognized contributor to response variability in cell therapy, specifically the development of GID. Indeed, we previously demonstrated that homozygous rs6265 (Met/Met) parkinsonian rats engrafted with wild-type (WT; Val/Val) DA neurons uniquely exhibited GID compared to their WT counterparts. To further expand these findings, I investigated the impact of rs6265 in both the host and donor on DA neuron transplantation for my thesis research. I additionally studied whether exogenous BDNF treatment would mitigate GID behavior in the Met/Met parkinsonian rats engrafted with WT DA neurons. In both studies, rats were rendered unilaterally parkinsonian using 6-hydroxydopamine (6-OHDA), engrafted with intrastriatal embryonic ventral mesencephalic (eVM) neurons from E14 WT or Met/Met donors, and assessed for amelioration of levodopa-induced dyskinesia (LID) (graft function) and induction of graft-induced dyskinesia (GID) (graft dysfunction). For the second experiment, exogenous BDNF was administered directly above the grafted DA neurons through a cannula connected to a subcutaneous osmotic minipump for four weeks following engraftment. From these experiments, I first determined that (1) the homozygous rs6265 Met/Met genotype, whether present in the host or donor, elicits superior graft-derived functional benefit compared to WT parkinsonian hosts, and (2) Met/Met parkinsonian rats engrafted with WT DA neurons curiously remain the only host/donor combination to exhibit significant GID behavior. Moreover, I discovered that (3) exogenous BDNF administration is not a feasible treatment for GID as BDNF exacerbated GID in Met/Met parkinsonian rats engrafted with WT DA neurons, and (4) evidence suggests that dysregulated DA/glutamate co-release and/or excess DA release is associated with GID induction, a phenomenon that corresponds with clinical trials where individuals with GID benefited from buspirone (a DA antagonist) administration. Because several clinical grafting trials for PD are now planned or ongoing, uncovering the underlying mechanisms responsible for GID will be necessary to optimize cell transplantation as a safe alternative therapeutic in PD. Collectively, the knowledge gained from my research offers guidance moving forward for the development of promising precision-medicine-based therapies that effectively treat the majority, not only a subset, of patients with PD.
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