| Parkinson's disease (PD) affects more than 1% of the population over 50 years of age in the U.S. The cardinal symptoms of PD, including resting tremor, bradykinesia, rigidity, and postural instability, arise when 70-80% of striatal dopamine is depleted and 40-50% of dopaminergic nigrostriatal neurons are dead. Although post-mortem studies, toxin models, and PD-associated genetic mutations have given insight into the mechanisms by which dopaminergic neurons degenerate, the factors that cause specific nigral neurodegeneration remain unknown. One major hypothesis is that this is determined by the presence of dopamine itself. Dopamine is readily oxidized into a variety of neurotoxic compounds that could contribute to oxidative stress seen in PD brains. Previous work in our lab has shown that dopamine depletion decreases the generation of reactive oxygen species and protects dissociated dopaminergic neurons in culture against the parkinsonian mimetic MPP+. The first part of this thesis, however, demonstrates that depletion of dopamine in mice by either pharmacological or genetic means does not attenuate nigrostriatal damage following MPTP exposure. MPTP is considered one of the best available PD toxin models because it recapitulates many of the features of PD. Thus, these results strongly suggest that dopamine does not contribute to the death of nigral neurons and other factors must account for the specificity of neurodegeneration observed in PD. The second part of this thesis examines MPTP-induced "dying back" axonopathy in the nigrostriatal pathway. As is seen in idiopathic PD, MPTP causes a greater loss of striatal dopaminergic innervation than of nigral cell bodies. This suggests that therapies that preserve synaptic function or delay axonal degeneration may slow disease progression. We found that dopaminergic striatal innervation is protected following MPTP exposure in mice that have delayed Wallerian degeneration (WldS) but nigral neuronal soma are not. These results support the hypothesis that axons have a self-destruct program that is independent of classical programmed cell death pathways. However, this also demonstrates that axon protection is insufficient to protect cell bodies and supports the idea that protection of synapses needs also to be considered for effective PD treatment. |
