Objective/Rationale:
In an attempt to replace dopamine expressing neurons that die in Parkinson’s disease patients have received grafts of fetal dopamine-containing cells. Over time, these patients die from their PD or other causes and it is imperative that their brain’s be evaluated for graft survival and neuronal function. Two patients who received fetal transplants 14 years ago have recently died and their brain’s have been rapidly collected and are in my laboratory. This grant will cover the costs to process and evaluate these brains.
Project Description:
Three brains from individuals with long term fetal transplants are already in the lab of the PI. Two are PD patients received fetal nigral transplants 14 years prior to death. One is a Huntington’s disease case that received fetal striatal transplants 11 years prior to transplant and will serve as a control. We will use staining procedures to identify the transplants, determine whether they express dopaminergic markers in a normal fashion, determine the presence of absence of inflammatory respeonses, and determine whether the grafted cells express markers of Parkinson’s disease. Additionally, we have already demonstrated that grafted cell can form Lewy bodies, this study will quantify those findings.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
These experiments will determine whether grafted cells get Parkinson’s disease in a manner similar to host nigral cells. These studies will support or refute the hypothesis that PD can be transmitted from the host to the graft. The findings from these studies will impact on the viability of cell replacement strategies being a potent option for the treatment of PD.
Anticipated Outcome:
Based upon our-existing data, we anticipate that the grafted cells in the PD cases will form Lewy bodies and that this observation will negatively impact cell transplantation strategies. However, they will give us greater insight into disease pathogenesis.
Final Outcome
This project assessed the presence of Lewy bodies, the cardinal pathological feature in Parkinson’s disease in young dopamine cells that were grafted in PD patients for therapy. The researchers found, in two cases in which the grafts survived for greater than 10 years, that seven to eight percent of grafted dopamine neurons expressed alpha-synuclein and ubiquinin-positive Lewy bodies. This percentage is similar to what is seen in within the nigra in PD.
The researchers also examined grafts from patients who survived for shorter intervals. At 18 months, no alpha-synuclein was observed in any of the grafted neurons. At four years, only soluble alpha-synuclein was observed. Thus aggregated alpha synuclein is formed somewhere between four and 10 years survival, much earlier than what is seen in the PD nigra. The formation of these Lewy bodies does not appear to be due to generalized inflammatory processes, as a graft that survived in the Huntington’s disease brain for over 10 years showed similar inflammatory responses but never displayed Lewy bodies.
These data support the concept that processes that negatively impact host nigral neurons may be influencing grafted neurons over the long term as well. However, all graft cases had numerous surviving grafted neurons with good striatal reinnervation. The findings of Lewy bodies may impact our understanding of disease pathogenesis but likely will not have a major impact on cell replacement strategies for treating PD.