Objective/Rationale:
Finding ways to protect dopaminergic neurons from degeneration could provide new therapies for Parkinson’s disease (PD). Transforming growth factor betas (TGF-betas) are essential factors for the survival and development of midbrain dopaminergic neurons. Our preliminary studies show that disruption of TGF-beta signaling in neurons promotes dopaminergic neurodegeneration and motor deficit in adulthood, we are therefore investigating the potential benefits of increasing TGF-beta signaling in dopaminergic neurons in a pre-clinical model of Parkinson’s disease.
Project Description:
The biological outcome of TGF-beta signaling is highly context- and cell-type dependent. We will employ a genetic approach to increase TGF-beta signaling specifically in dopaminergic neurons, to circumvent the confounding effects of global TGF-beta signaling activation observed in other studies. We will determine whether activation of TGF-beta signaling pathway in dopaminergic neurons will protect them against a Parkinsonism inducing neurotoxin. We will evaluate movement symptoms with a battery of behavioral tests and assess the progression of neurodegeneration by the number and connectivity of dopamine-producing brain cells.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
TGF-beta has multiple associations with Parkinson's disease as well as the nigrostriatal system. However, no direct causal relationship has been established so far between TGF-beta signaling and the pathogenesis of Parkinson's disease. In this project we will test whether increased neuronal TGF-beta signaling reduces PD-related neurodegeneration and motor deficits. The results from this project will therefore enhance our understanding of the pathogenesis of the disease and help to discover new drug targets.
Anticipated Outcome:
This project should shed novel insights into the role of TGF-beta signaling in the pathogenesis of Parkinson’s disease and validate TGF-beta signaling as a potential target for a disease-modifying therapy for the disease. The completion of this project will provide critical data essential for larger treatment studies using targeted delivery of TGF-beta signalling activators or small molecule agonists for this pathway now under development.