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Nigrostriatal Dopaminergic Degeneration and Alpha-synuclein Aggregation in Mice with Reduced TrkB Signaling

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and deposition of cytoplasmic protein aggregates termed Lewy bodies (LB) in a brain structure termed substantia nigra pars compacta (SNpc). In order to understand the pathogenesis of PD and to find an effective treatment for the disease, it is essential to have an animal model which mimics the major features of the disease. Unfortunately, currently available PD animal models fail to display progressive degeneration of the dopaminergic neurons in association with formation of LB-like protein aggregates. TrkB is the receptor for brain-derived neurotrophic factor and neurotrophin-4/5, two of the four neurotrophins which promote survival of neurons in the mammalian nervous system. We have generated a mouse mutant which expresses the TrkB receptor at less than 25% of the normal amount. Our preliminary data indicate that the mutant loses a significant number of dopaminergic neurons in association with deposition of LB-like protein aggregates in the SNpc when it is one year old. Interestingly, the degeneration does not occur in the mutant at 8 months of age. This proposed project will determine if the dopaminergic neurons in the SNpc are progressively degenerated and if neurodegeneration also occurs in other brain regions by analyzing the mutant mouse at 12 and 15 months of age. If the mutant displays progressive and selective degeneration of dopaminergic neurons in the SNpc, it would be a useful animal for determining the pathogenesis of PD and for testing potential drugs for the disease.

Final Outcome

Previous evidence suggested that reduced levels of the growth factor brain-derived neurotrophic factor (BDNF) was associated with loss of dopamine neurons. Dr. Xu generated mice genetically engineered to express reduced levels of the BDNF receptor, trkB, and found a 20- to 30-percent reduction in nigral dopamine neurons. Some reduction in alpha-synuclein aggregates was also seen. However Dr. Xu was not able to demonstrate a significant PD-relevant phenotype in the mice with reduced expression of TrkB receptor.


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