A Novel Animal Model to Identify the Contribution of Iron Mismanagement to Neurotoxicity and a-synuclein deposition in Basal Ganglia

Iron in the substantia nigra is an etiological factor in PD. In addition, iron is established as a key determinant in neurotoxin-based models of PD. Iron is critical for cells to interact with oxygen to produce energy, but because of its ability to interact with oxygen, iron is the major risk factor associated with induction of oxidative stress.

Numerous studies have shown that oxidative stress is the leading cause of cell death for neurons in PD and the neurotoxin models. The primary mechanism for sequestering iron intracellularly, and thereby limiting the ability of iron to induce oxidative stress, is the protein, ferritin. In recognition of the importance of ferritin, an animal model that overexpresses ferritin in the dopaminergic neurons of the substantia nigra is less vulnerable to the neurotoxins that usually result in the death of these cells. We have developed an animal model to directly test the contribution of ferritin to histopathology of PD.

We introduce to PD research in this application a new type of model that expresses only 20 percent of the normal amount of ferritin in the brain but has a normal amount of iron. Therefore these models have a similar imbalance of iron to ferritin that we have reported in the human brain in PD. Consequently, these animals should have the same environment of oxidative stress that occurs in the brain in PD. This model could provide the opportunity to determine whether iron imbalance in the brain is a contributor to PD, a causative agent, or is simply associated with the disease process. Longer-term goals are to provide an animal model whose brain mimics the oxidative stress environment that promotes the loss of brain cells and leads to PD and to have a model  similar to the PD brain in which to test pharmaceutical intervention strategies for neurotoxin exposure and PD.