Funded Studies
Objective/Rationale:
We recently reported that neuropathological changes gradually propagate from Parkinson disease patients’ brains to grafted neurons. Over one decade after graft surgery, we found that transplanted neurons expressed alpha-synuclein in their cell bodies and exhibited abnormal aggregates containing this protein. Thus, the grafts contained features akin to those found in the PD brain. We do not know how the abnormal proteins are transferred from host brain to graft cells. One hypothesis is that misfolded alpha-synuclein is transmitted from PD host cells to grafted neurons.
Project Description:
We will use a pre-clinical model that expresses human wild-type alpha-synuclein. We will transplant normal, wild-type, tissue into transgenic mouse hosts (similar to the clinical situation). We will examine if alpha-synuclein aggregates appear in grafted cells, in particular dopaminergic neurons. We also plan to graft alpha-synuclein-overexpressing cells to the brains of wild-type mice, in order to examine if the abnormal alpha-synuclein can transfer into neurons in the host brain. The mice will survive for different extended time periods (partly depending on age at time of grafting), to monitor the influence of time on the aggregation process. Finally, we will section the brains and stain them with different antibodies. We will monitor alpha-synuclein aggregation, what types of cells that it affects and how it is influenced by the delay after surgery.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
We hypothesize that alpha-synuclein aggregation and deposition in grafted dopaminergic neurons are triggered by misfolded alpha-synuclein in the host brain. We believe that a similar mechanism operates also within the brains of PD patients. We will generate pre-clinical models to address how the disease to transfer between cells. These models can be used to test novel neuroprotective therapies against PD. The knowledge obtained will also be of great value for future therapeutic transplantation to treat PD.
Anticipated Outcome:
If we can mimic the findings we obtained in the grafted PD patients in pre-clinical models of the disease we will have an excellent system in which we can study how cellular PD changes develop. Using this model system, we hope to be able to identify the mechanisms that allow the disease to transfer between cells. Thus we may understand the etiology of PD better and use this knowledge to develop new therapies that slow disease progression.
Final Outcome
Autopsies of Parkinson’s disease (PD) patients grafted with fetal dopaminergic neurons more than a decade before their deaths revealed Lewy bodies containing deposits of alpha-synuclein not only in the substantia nigra but also within the graft. These results and others support the concept of a prion-like propagation of misfolded alpha-synuclein during PD progression, as has been proposed for other pathogenic proteins involved in neurodegenerative diseases, such as Alzheimer’s Disease and tauopathies. In an attempt to mimic the clinical condition, we grafted wild-type embryonic midbrain tissue into the striatum of transgenic mice overexpressing the wild-type human alpha-synuclein protein. We are currently analyzing these transplants to assess whether human alpha-synuclein has been transmitted from the host brain to the grafted wild-type post-mitotic cells.