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.

GRP78 clustering at the cell surface of neurons transduces the action of exogenous alpha-synuclein.

VALTORTA , FLAVIA;
2014-01-01

Abstract

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.
parkinson; neurodegeneration; neuron
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/4408
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