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can cause phenotypes similar to that of patients with Gaucher disease41). However, an association between saposin D and human disease had not been revealed. Recently, I and my colleagues iden-tified patients with three independent autosomal familial Parkinson’s disease associated with patho-genic mutations of saposin D (PARK24)25). The proband had p.Q453P mutation, while the second and third patients had a p.C451_L447 deletion and p.C412Y mutation, respectively. The clinical pheno-types of patients with pathogenic saposin D muta-tions mimicked that of idiopathic Parkinson’s disease, but the age of onset was relatively earlier than the usual idiopathic type. 123I-MIBG cardiac scintigraphy revealed the degeneration of cardiac sympathetic nerves and a DAT scan depicted the degeneration of striatonigral neurons, similar to idiopathic Parkinson’s disease. Saposin has three disulfide bonds that are important for its function. The p.Q453P mutation disrupts the formation of an α-helix structure in the saposin D domain. The p.C451_L477del mutation ablates two cysteine resi-dues, resulting in the breaking of two disulfide bonds, which disrupts the α-helix structure in the saposin D domain. The p.C412Y mutation also potentially ablates a disulfide bond in the saposin D domain. Thus, mutations in saposin D are likely to have a major impact on prosaposin function.Prosaposin, a precursor protein of saposins, is trafficked to the lysosome via the endoplasmic reticulum (ER)-Golgi-endosome network, also known as the membrane trafficking system. The association of sphingomyelin is important for proper membrane trafficking of prosaposin42). A previous report suggested that the interaction site with sphingomyelin is within the saposin D domain. Saposin D with a disrupted structure might not bind to the membrane, resulting in mislocalization of prosaposin. Indeed, in dopaminergic neurons derived from induced pluripotent stem cells of patients with PARK24-linked Parkinson’s disease, the pathogenic mutant prosaposin localized to the ER; in contrast, wild-type prosaposin localized to lysosomes in control neurons. Furthermore, fibro-blast cells obtained from patients with PARK24-linked Parkinson’s disease had abnormally enlarged autolysosomes and significantly increased expres-sion of LAMP2, a lysosomal membrane protein, compared with control cells. Moreover, dopami-nergic neurons derived from induced pluripotent stem cells of patients with PARK24-linked Parkin-son’s disease exhibited significantly increased expression of an aggregating form of α-synuclein compared with normal dopaminergic neurons. These results suggest that pathogenic heterozygous mutations in saposin D will impair its function in lysosomes or endow a toxic function that results in dopaminergic neuronal degeneration with aggrega-tion of α-synuclein due to lysosomal dysfunction25).Conformational changes of α-synuclein tend to results in fibrilization. Early intermediates in the fibril formation pathway of α-synuclein are known as protofibrils, which can propagate from cell to cell like prion proteins43). Accordingly, the propagation of α-synuclein might be one of the most important mechanisms underlying Parkinson’s disease progres-sion. Postmortem histological analyses performed by Braak and colleagues concluded that α-synu-clein aggregation might start from two neuronal circuits: the olfactory and vagus systems44). Indeed, hyposmia and constipation are some of the earliest symptoms of Parkinson’s disease3). Furthermore, studies of two large cohorts found that truncal vagotomy might prevent the prevalence of Parkin-son’s disease45, 46). In addition, following direct inoc-ulation of α-synuclein fibrils and Lewy bodies into animal brains, the spread of α-synuclein aggrega-tions in areas along the neuronal circuit was observed several months after injection47). To reveal the speed of propagation of α-synuclein in the mouse striatum, I and my colleagues performed a callosotomy before or after the inoculation of α-synuclein fibrils48). Interestingly, callosotomy 24 hours before the injection was able to prevent the propagation of α-synuclein to the contralateral stri-atum; however, in the mice with callosotomy 24 hours after injection, α-synuclein was extensively aggregated. These findings indicate the speed by which α-synuclein fibrils spread is very fast, allowing them to propagate from neuron to neuron within 24 hours. In addition, to reveal the manner of propagation in vivo, the contralateral striatum was treated with botulinum toxin 3 days before and 1 day after α-synuclein inoculation in the stri-atum. Pre-treatment with botulinum toxin, which inhibits synaptic vesicle exocytosis by cleaving 533Propagation of α-synuclein