Cystatin C Triggers Neuronal Degeneration in a Model of Multiple System Atrophy

Multiple system atrophy is an intractable neurodegenerative disease caused by alpha-synuclein (alpha-syn) accumulation in oLigodendrocytes and neurons. With the use of a transgenic mouse model overexpressing human alpha-syn in oligodendrocytes, we demonstrated that oligodendrocytic alpha-syn inclusions induce neuronal alpha-syn accumulation, resulting in progressive neuronal degeneration. The mechanism through which oligodendrocytic alpha-syn inclusions trigger neuronal alpha-syn accumulation leading to multiple system atrophy is unknown. In this study, we identified cystatin C, an oligodendrocyte-derived secretory protein that triggers alpha-syn up-regulation and insoluble alpha-syn accumulation, in neurons of the mouse central nervous system. Cystatin C was released by mouse oligodendrocytes overexpressing human alpha-syn, and extracellular cystatin C increased the expression of the endogenous alpha-syn gene in wild-type mouse neurons. These neurons then accumulate insoluble alpha-syn and may undergo apoptosis. Cystatin C is a potential pathogenic signal triggering neurodegeneration in multiple system atrophy.