Impairment of Neurogensis in the Olfactory Bulb of Transgenic Mice Overexpressing Human Wildtype Alpha Synuclein Under the Thy-1 Promoter

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that impairs motor function. Patients with PD display motor symptoms including bradykinesia, akinesia, rigidity, resting tremor, and postural instability. In addition, recent studies have found early non-motor symptoms in patients with PD including olfactory impairments, gastrointestinal dysfunction, sleep disturbances, anxiety and depression. The genetically engineered alpha-synuclein overexpressing mice (ASO) under the Thy-1 promoter have high levels of alpha-synuclein and demonstrate distinctive proteinase K-resistant alphasynuclein inclusions throughout the brain including the thalamus, basal ganglia, cortex and olfactory bulb (Rockenstein et al., 2002). These mice demonstrate early and progressive motor impairments without the loss of nigrostriatal dopaminergic neurons at nine months of age (Fleming et al., 2004). The ASO mice under the Thy-1 promoter demonstrate olfactory impairments in olfactory tests and thus may present an early model of Parkinson’s disease (Fleming et al., 2005). It has been documented that Parkinson’s patients have impairments outside of the nigrostriatal pathway. One area that can be affected is the olfactory senses. The olfactory neurons are renewed throughout life: the neurons originate from the subventricular zone (SVZ) and then migrate along the rostral migratory stream (RMS), which are surrounded by olfactory ensheathing glia, and eventually reach the olfactory bulb (Gritti et al., 2002). Recent studies have shown that the ASO mice under the PDGFß promoter have impairments in neurogenesis of the olfactory bulb and hippocampus, presenting a mouse model of PD with impairments outside the of the nigrostriatal pathway (Winner et al., 2004). The goal of the project outlined in this proposal is to investigate whether animals exhibiting an accumulation of alpha-synuclein in the olfactory bulb demonstrate impairments in the olfactory senses. This study can provide a better understanding of early symptoms of Parkinson’s disease. It will also provide better criteria for testing and diagnosing the earlier stages of Parkinson’s disease and may allow for early therapeutic interventions.