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tigations revealed that neuronal degeneration occur-ring with the aggregation of α-synuclein might propagate along neuronal circuits. Specifically, conformational changes that transform the normal structure of α-synuclein can exacerbate self-aggre-gation. Moreover, abnormally structured α-synu-clein, called a seed, can propagate from neuronal cell to cell, like a prion protein12, 13). In this review, I focus on the propagation and aggregation of α-sy-nuclein in pathomechanisms of Parkinson’s disease.Lewy body and α-synucleinLewy body is a classical pathological hallmark of Parkinson’s disease14). Dsytrophic neurites, a known precursor of this aggregation, include ubiquitin and α-synuclein15). Ubiquitin plays essential roles in the ubiquitin-proteasome system, which performs protein degradation. Abnormally structured proteins are usually conjugated with ubiquitin by E3 ligase, resulting in their ATP-dependent degradation by proteasomes16). Ubiquitin is typically localized within the core of Lewy body, whereas α-synuclein localizes to the outermost layer. Furthermore, the structure of Lewy body in the brainstem is slightly different from that of Lewy body in the cortex. Brainstem-type Lewy bodies present as intracyto-plasmic, single or multiple, spherical or elongated, eosinophilic masses with a dense core and periph-eral halo in hematoxylin and eosin staining; whereas, cortical-type Lewy bodies exhibit eosinophilic irregular structures without a conspicuous halo or core. Previous electron microscopic analyses revealed that Lewy body has outer filamentous structures with dense cores. Further immuno-pathological studies identified the main component of the filamentous structure as α-synuclein15). Notably, it is difficult to precisely observe Lewy bodies using transmission electron microscopy because of issues discriminating these structures from background and other abnormal features. However, the recently developed correlative light and electron microscopy method can merge elec-tron microscopic analysis with immunohistochem-istry. This method revealed the involvement of Lewy bodies with many types of organelles, such as mitochondria, lysosomes, autophagosomes, membranes, and synaptic vesicles. Furthermore, Lewy body formation might be triggered by the disruption of interactions between α-synuclein and lipid membranes17). Thus, mechanisms underlying α-synuclein aggregation may be the most important pathogenic pathway in Parkinson’s disease. α-synu-clein, an amphipathic protein with a molecular weight of 14 kDa, contains two α-helices at its N-terminus that are important for binding to lipid membranes18). In cytosol, α-synuclein moves dynamically and does not have a specific structure. However, conformational alterations of the struc-ture of α-synuclein, which includes β-sheet struc-tures, are associated with self-aggregation. Furthermore, α-synuclein exhibiting an abnormal β-sheet structure can induce other normal α-sy-nuclein to adopt the abnormal β-sheet structure, which exacerbates aggregation (also known as fibrilization). Previous investigations revealed that the disruption of interactions between α-synuclein and lipid membranes can induce conformational changes of α-synuclein19). Thus, elucidating the association between lipid metabolism and α-synu-clein aggregation might be helpful for under-standing the pathomechanisms of Parkinson’s disease. Clinical reports indicate that genetic dysfunction of several lipid enzymes is associated with familial Parkinson’s disease. Pathogenic muta-tions of PLA2G6, a phospholipase, cause autosomal recessive familial Parkinson’s disease20). Whereas biallelic pathogenic mutations of glucocerebrosi-dase (GBA) cause Gaucher disease, heterozygous GBA mutation is a known risk factor for Parkin-son’s disease21, 22). Moreover, enzymes and func-tional proteins in glycolipid metabolic pathways, such as arylsulfatase A23), SMPD-124), and prosa-posin25), have been associated with Parkinson’s disease. Thus, dysregulation of phospholipid and/or glycolipid metabolic pathways might be an important mechanism underlying the aggregation of α-synuclein.PLA2G6 is a phospholipid enzyme that hydro-lyzes the sn-2 ester bonds of phospholipids, gener-ating free fatty acids and lysophospholipids26). PLA2G6 was identified as the causative gene of infantile neuroaxonal dystrophy, and as well as neurodegeneration with brain iron accumulation27). PARK14 are associated with early-onset autoso-mal-recessive familial Parkinson’s disease, which can also arise from mutations of PLA2G620, 28). 531PLA2G6 and α-synuclein aggregation