Most Parkinsons disease patients lose their sense of smell, sometimes decades before they develop the symptoms typically associated with the disease, such as tremors and difficulty walking. Olfactory deficits, hyposmia or anosmia, is now recognized as a feature of early Parkinsons disease and an indication that the disease is progressing insidiously. In this FY16 PRP Focused Idea Award application, we will examine the underlying causes for olfactory deficits seen in Parkinsons patients. The focus of our application is directly in line with the Focus Area of Identification and evaluation of mechanisms in early Parkinsons disease involving olfactory, microbiome, gastrointestinal, andor autonomic nervous systems. In this grant, we will examine how a protein known as alpha-synuclein, that forms abnormal deposits that are a signature of Parkinsons disease, impacts nerve connections or synapses in the olfactory system. We suggest that in Parkinsons disease, due to the presence of these abnormal alpha-synuclein deposits, both the structure and function of olfactory nerve connections is not proper. We will examine this question through our complementary expertise in the olfactory system and alpha-synuclein biology, using high resolution microscopic methods on mouse models that express mutant forms of alpha-synuclein that are linked to the disease. When we have successfully finished this study, we anticipate having a detailed picture of the synaptic abnormalities in the olfactory system in an animal model of early Parkinsons disease. This will allow us to treat the loss of smell in early Parkinsons disease patients in 5-10 years. But more importantly, as the nose and the olfactory system are thought to be a conduit through which alpha-synuclein deposits spreads, eventually reaching the mid-brain, a greater understanding of this pathway will permit us to slow the progression or even prevent Parkinsons disease.