title: Cystatin C triggers neuronal degeneration in a model of multiple system atrophy.
abstract: Multiple system atrophy is an intractable neurodegenerative disease caused by α-synuclein (α-syn) accumulation in oligodendrocytes and neurons. With the use of a transgenic mouse model overexpressing human α-syn in oligodendrocytes, we demonstrated that oligodendrocytic α-syn inclusions induce neuronal α-syn accumulation, resulting in progressive neuronal degeneration. The mechanism through which oligodendrocytic α-syn inclusions trigger neuronal α-syn accumulation leading to multiple system atrophy is unknown. In this study, we identified cystatin C, an oligodendrocyte-derived secretory protein that triggers α-syn up-regulation and insoluble α-syn accumulation, in neurons of the mouse central nervous system. Cystatin C was released by mouse oligodendrocytes overexpressing human α-syn, and extracellular cystatin C increased the expression of the endogenous α-syn gene in wild-type mouse neurons. These neurons then accumulate insoluble α-syn and may undergo apoptosis. Cystatin C is a potential pathogenic signal triggering neurodegeneration in multiple system atrophy.
authors.affiliation: Laboratory of Research Resources, Research Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan.
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Laboratory of Research Resources, Research Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan.
authors.forename: Chenghua
authors.initials: C
authors.lastname: Jin
authors.affiliation: Laboratory of Research Resources, Research Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan. Electronic address: yazawaik@ncgg.go.jp.
authors.forename: Ikuru
authors.initials: I
authors.lastname: Yazawa
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D055316:Cystatin C / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D055316:Cystatin C; C497604:SNCA protein, human; D051844:alpha-Synuclein