Iron is an element naturally present in the brain and is required for its proper function. Iron levels, however, must be tightly controlled because excessive amounts, as observed in Parkinson’s disease (PD), are toxic and actively contribute to neuronal death. Approaches to block iron accumulation could therefore lead to promising cures; it is still unclear, however, which of the specific proteins that control iron levels in the brain should be targeted by these therapies. This project will study a particular protein controlling iron — transferrin receptor 2 — to determine if it is a valid therapeutic target.
To specifically focus on this protein, we have generated a new pre-clinical model in which the protein has been genetically eliminated only in dopamine neurons. We will reproduce features of PD by either administrating the PD-related neurotoxin MPTP or increasing levels of the alpha-synuclein protein. The use of different strategies to model PD will tell us how our protein influences different aspects of PD progression. We will study the brains of these models to understand whether deletion of the protein is beneficial.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Current approaches to reduce iron levels in PD rely on drugs whose action is not confined to dopamine neurons. These compounds therefore reduce iron levels in general and present strong side effects. Conversely, our project will validate the therapeutic potential of a pathway that is responsible for iron transport and accumulation specific in the neurons affected by PD and will lay a foundation for more effective cures.
In the proposed study we expect to clarify whether targeting our protein of interest, specifically at the level of neurons affected by PD, delays disease progression. This information may be instrumental to devise more effective and tolerable therapeutic intervention to prevent iron accumulation. If successful, future studies will validate the target in different organisms and design specific molecules that can inhibit the function of this protein pharmacologically.