multiplication of the alpha-synuclein-encoding gene is frequent cause of early onset Parkinson’s disease. Recent evidences point to the pathogenic role of excess alpha-synuclein also in sporadic Parkinson’s disease. Alpha-synuclein is a cytosolic protein which has been show to be released from neurons. Here we provide evidence that extracellular alpha-synuclein induces an increase in surface-exposed glucose-related protein of 78 kDa (GRP78), which becomes clustered in microdomains of the neuronal plasma membrane. Upon interacting with alpha-synuclein, GRP78 activates a signalling cascade leading to cofilin 1 inactivation and stabilization of microfilaments, thus affecting morphology and dynamics of actin cytoskeleton in cultured neurons. Down-regulation of GRP78 abolishes the activity of exogenous alpha-synuclein, indicating that it is the primary target of alpha-synuclein. Inactivation of cofilin 1 and stabilization of actin cytoskeleton are present also in fibroblasts derived from genetic Parkinson’s disease patients, which show a dramatic increase in stress fibers. Similar changes are displayed by control cells incubated with the medium of Parkinson’s disease fibroblasts, only when alpha-synuclein is present. The accumulation of alpha-synuclein in the extracellular milieu, its interaction with the plasma membrane, and alpha-synuclein-driven clustering of GRP78 appear therefore responsible for the dysregulation of actin turnover, leading to early deficits in synaptic function that precede neurodegeneration.
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