Functional analysis of glia in alpha-synucleinopathy

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Parkinson's disease is the most common movement disorder and is characterized clinically by tremor and bradykinesia, as well as by cognitive decline in more widespread forms of the disease. Classic neuropathological features of Parkinson's disease include intraneuronal Lewy bodies formed by intraneuronal deposition of abnormally phosphorylated and aggregated α-synuclein protein, as well as gliosis. Glial pathology has generally been considered a secondary, or reactive, change. However, recent advances in understanding normal and pathological glial biology have instead suggested that glia may play an active role in neurological disorders, including Parkinson's disease. Here we take a genetic approach to define proteins and pathways mediating the influence of glia on Parkinson's-associated neurodegeneration. Taking advantage of the advanced molecular and genetic tools, short lifespan, and conserved glial biology in Drosophila we will identify glial proteins and pathways that can influence α-synuclein neurotoxicity in aging adult brains. In proof of principle studies, we will validate a novel system for studying non-cell autonomous neurodegeneration in α-synucleinopathy. In addition, based on the observation that many genes implicated in Parkinson's disease through genome wide genetic association studies are expressed predominantly or substantially in glial cells, we will test the effect of upregulating and downregulating these genes in glia on α-synuclein induced neurotoxicity. These studies will develop a novel methodology for studying the effect of glia on the neurodegeneration associated with Parkinson's disease and will ultimately expand the array of molecular and cellular targets relevant for therapy development in this common and devastating disorder.