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α-Synuclein Aggregation and Propagation in the Pathomechanisms of Parkinson’s Disease　Parkinson’s disease is a neurodegenerative disorder that manifests with motor dysfunction, such as bradykinesia, tremor, and rigidity. Furthermore, patients experience many non-motor problems, including dementia, psychosis, pain, sleep disturbances, and autonomic dysfunction, which impact their quality of life. Thus, disease-modifying therapies for Parkinson’s disease are needed. The pathological hallmark of this disease is dopaminergic neuronal loss with intraneuronal aggregations, known as Lewy bodies, which contain proteins and lipids. Recently, it was revealed that several membranous organelles, such as mitochondria, lysosomes, autophagosomes, and synaptic vesicles, are involved in Lewy bodies. Moreover, the main protein component of Lewy body, α-synuclein, binds to lipid membranes via two α-helices at the N-terminus. Interestingly, disrupted associations between lipid membranes and α-synuclein might trigger the formation of Lewy body. Accordingly, α-synuclein aggregation and lipid-synuclein interactions are important for the pathomechanisms of Parkinson’s disease. In this review, I will focus on (1) the role of lipid metabolism in Parkinson’s disease, and (2) α-synuclein aggregation and propagation in Parkinson’s disease.530Juntendo Medical Journal2021. 67(6), 530-536Special ReviewsIntroductionParkinson’s disease is the second most prevalent neurodegenerative disorder after Alzheimer’s disease. Neurodegeneration within the substantia nigra pars compacta is a specific finding of Parkinson’s disease; accordingly, affected patients show hypoki-netic abnormal movements such as bradykinesia, tremor, and rigidity1). Although motor dysfunctions are ameliorated by administration of levodopa, marked degeneration of dopaminergic neurons will reduce its effectiveness, resulting in motor fluctua-tions2) that directly impair the quality-of-life of patients. Furthermore, as Parkinson’s disease progresses, the expansion of neurodegeneration from the peripheral to central nervous system induces various non-motor symptoms, such as autonomic dysfunction, dementia, anxiety, and Key words: parkinson’s disease, α-synuclein, prosaposin, PLA2G6, lewy bodyDepartment of Neurology, Juntendo University Graduate School of Medicine, Tokyo, JapanCorresponding author: Taku HatanoDepartment of Neurology, Juntendo University School of Medicine2-1-1 Hongo, Bunkyo-ku Tokyo, 113-8421, JapanTEL: +81-3-3813-3111　FAX: +81-3-5800-0547　E-mail: thatano@juntendo.ac.jp353rd Triannual Meeting of the Juntendo Medical Society “Medical Research Update”〔Held on May 22, 2021〕〔Received　Sep. 24, 2021〕〔Accepted　Oct. 13, 2021〕J-STAGE Advance published date: Dec. 17, 2021Copyright © 2021 The Juntendo Medical Society. This is an open access article distributed under the terms of Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original source is properly credited. doi: 10.14789/jmj.JMJ21-0029-Rsleep disturbances3). Almost none of the non-motor symptoms of Parkinson’s disease are alleviated by symptomatic treatment, therefore, patients with Parkinson’s disease usually have many unmet medical needs4). In this context, disease-modifying therapy is needed for Parkinson’s disease. To develop such therapies, the pathomechanisms of this disease must be elucidated. The Lewy body is a key structure underlying the neuropathology of Parkinson’s disease. Although Lewy body contain many lipids and proteins, the most abundant component is α-synuclein5). Furthermore, reported pathogenic α-synuclein mutations, such as p.A30P, p.E46K, p.H50Q, p.G51D, and p.A53T, have been associated with autosomal dominant familial Parkin-son’s disease6-11). Thus, aggregation of α-synuclein might be the dominant pathomechanism of Parkin-son’s disease. In addition, recent pathological inves-Taku HATANO