Parkinson's disease is characterized by the premature neurodegeneration of nigrostriatal dopamine neurons. In order to discover what may be causing this cellular loss or provide a treatment that may decrease the progression of the disease, studies in our laboratory have been focused on identifying factors that are important for the survival and plasticity of dopamine neurons. In order to carry out this goal, we have been utilizing three mouse models. The first, is the weaver mutant mouse in which abnormal development of the dopaminergic nigrostriatal fibers is first observed followed by degeneration of dopaminergic neurons in a similar pattern to what is found in Parkinson's disease, TGF-alpha, during the time of dopaminergic neuronal degeneration. In addition, we have found that these mice also have decreased levels of thyroid hormone, a potent regulator of brain development. Therefore, we have proposed studies aimed at discovering whether the decreases in either TGF-alpha or thyroid hormone are responsible for the neurodegeneration of dopamine neurons in the weaver mutant mouse. Recently, another mutant mouse has been discovered, waved-1, which has a deficiency in TGF-alpha expression. The availability of this second mouse mutant, allows us to specifically test whether a deficiency in TGF-alpha alone results in the degeneration of dopamine neurons or increase their sensitivity to the neurotoxin, 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). There is evidence that the more resilient mesolimbic dopaminergic neurons are able to undergo collateral axonal sprouting in response to degeneration of the nigrostrital neurons. Thus, these dopaminergic neurons represent a potential target to stimulate collateral axonal sprouting after neurodegeneration of dopamine neurons in the substantia nigra. However, there is an age-related loss in the capacity of these neurons to spontaneously sprout. Therefore, in the last mouse model system we investigate what endogenous factors may be responsible for lesion-induced plasticity of dopamine neurons in young animals, how their induction in response to injury is regulated, and whether lesion-induced activation becomes the limiting factor in the age-related loss of dopaminergic plasticity. The results of these studies may reveal therapeutic possibilities for enhancing the recovery of dopamine neurons in neurodegenerative diseases in which spontaneous recovery does not normally occur.
NIH ExPorter
NIH ExPorter