We recently showed that certain brain neurons which are normally protected from Parkinson’s disease (PD) contain high levels of the developmental factor Gremlin-1. The goal of this project is the creation of a transgenic pre-clinical model in which expression of this putative neuroprotective factor has been genetically deleted from those brain cells. With this model, it will be possible in the future to explore the potential role of Gremlin-1 as a neuroprotective agent in PD.
In this project, we will cross breed three different pre-clinical models to create a transgenic model which no longer expresses Gremlin-1 in the region of the brain associated with PD. In addition, this model will produce a green fluorescent protein in Gremlin-1- deficient cells, making their characterization and analysis more easily accomplished in vitro and in vivo. Baseline studies will be conducted to verify that Gremlin-1 expression has indeed been knocked out in the appropriate brain cells without affecting other cells. In addition, this model will be studied to determine whether deletion of Gremlin-1 causes any unanticipated toxic effects on affected brain cells.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Once a transgenic model in which Gremlin-1 has been deleted is established, it will be possible to test whether the absence of endogenous stores of this factor render once-protected nerve cells of the brain vulnerable to PD injury. If so, then it suggests that exogenously administered Gremlin-1 may act as a novel neuroprotective agent to prevent the further loss of ‘at risk’ nerve cells in PD patients.
We fully expect that it will be possible to create the proposed transgenic line and establish that Gremlin-1 expression has been deleted without any associated toxicity in dopamine-producing nerve cells of the midbrain. If these experiments succeed, it will be possible to initiate studies to determine whether decreased Gremlin-1 causes reduced neuroprotection and increasing PD susceptibility, and conversely, whether increased Gremlin-1 ameliorates or prevents neurodegeneration in nerve cells at risk for PD.