The protein α-synuclein has been linked to many neurodegenerative disorders, including Parkinson’s disease, Lewy body dementia and other synucleinopathies. The physiological role of α-synuclein remains controversial, but it is known to form α-helical structures in its N-terminal region in the presence of lipids and to associate with membranes, leading to regulation of synaptic vesicle release. However, how membrane binding is regulated, and if it is affected in systems other than the central nervous system, remains unclear. This dissertation explores regulatory mechanisms of membrane binding of α-synuclein and investigates changes in α-synuclein membrane affinity in the central and enteric nervous system in the context of Parkinson’s disease. The synuclein protein family is comprised of three members: α-synuclein, β-synuclein, and γ-synuclein. We found all three synucleins bind to membranes and show preference towards small, highly curved membranes like those of synaptic vesicles. However, β-synuclein and γ-synuclein have reduced membrane affinity compared to α-synuclein. We demonstrated that all three synucleins can form homo-multimers upon membrane binding, as well as interact with each other to form hetero-multimers. Heteromultimerization of α-synuclein with β-synuclein or γ-synuclein results in decreased membrane association of α-synuclein while increasing the membrane association of β-synuclein and γ-synuclein. We suggest that these hetero-multimers serve as a tuning mechanism for membrane binding of α-synuclein and is a potential therapeutic target for future studies. α-synuclein is found not only in the central nervous system, but in the enteric nervous system as well. Gastrointestinal symptoms are among the earliest prodromal symptoms of Parkinson’s disease, often preceding disease diagnosis by a decade or longer. Previous studies suggest that Parkinson’s pathology may spread from the gut into the brain. We were interested in whether α-synuclein membrane binding is affected in the enteric nervous system, and if it could be used as a molecular marker of Parkinson’s disease. We used a variety of assays to investigate this, including both gastrointestinal and motor behavioral assays, in vitro liposome binding studies, biochemical analyses, immunohistochemistry, and subcellular fractionation of both mouse and human tissue. We showed both motor and gastrointestinal function impairments and reduced membrane binding of α-synuclein in the brain and gut of our mouse model. The reductions in membrane-binding were also observed in post-mortem human brain tissue and preliminarily in mucosal biopsies taken during routine screening colonoscopy in Parkinson’s disease patients. This study is the first biochemical assessment of α-synuclein in the gut and suggests a possibility of using membrane-binding as a molecular marker of Parkinson’s disease.