TY - JOUR

T1 - Exogenous α-synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release

AU - Ronzitti, Giuseppe

AU - Bucci, Giovanna

AU - Emanuele, Marco

AU - Leo, Damiana

AU - Sotnikova, Tatyana D.

AU - Mus, Liudmila V.

AU - Soubrane, Camille H.

AU - Dallas, Mark L.

AU - Thalhammer, Agnes

AU - Cingolani, Lorenzo A.

AU - Mochida, Sumiko

AU - Gainetdinov, Raul R.

AU - Stephens, Gary J.

AU - Chieregatti, Evelina

PY - 2014/8/6

Y1 - 2014/8/6

N2 - α-Synuclein is thought to regulate neurotransmitter release through multiple interactions with presynaptic proteins, cytoskeletal elements, ion channels, and synaptic vesicles membrane. α-Synuclein is abundant in the presynaptic compartment, and its release from neurons and glia has been described as responsible for spreading of α-synuclein-derived pathology. α-Synuclein-dependent dysregulation of neurotransmitter release might occur via its action on surface-exposed calcium channels. Here, we provide electrophysiological and biochemical evidence to show that α-synuclein, applied to rat neurons in culture or striatal slices, selectively activates Cav2.2 channels, and said activation correlates with increased neurotransmitter release. Furthermore, in vivo perfusion of α-synuclein into the striatum also leads to acute dopamine release. We further demonstrate that α-synuclein reduces the amount of plasma membrane cholesterol and alters the partitioning of Cav2.2 channels, which move from raft to cholesterol-poor areas of the plasma membrane. We provide evidence for a novel mechanism through which α-synuclein acts from the extracellular milieu to modulate neurotransmitter release and propose a unifying hypothesis for the mechanism of α-synuclein action on multiple targets: the reorganization of plasma membrane microdomains.

AB - α-Synuclein is thought to regulate neurotransmitter release through multiple interactions with presynaptic proteins, cytoskeletal elements, ion channels, and synaptic vesicles membrane. α-Synuclein is abundant in the presynaptic compartment, and its release from neurons and glia has been described as responsible for spreading of α-synuclein-derived pathology. α-Synuclein-dependent dysregulation of neurotransmitter release might occur via its action on surface-exposed calcium channels. Here, we provide electrophysiological and biochemical evidence to show that α-synuclein, applied to rat neurons in culture or striatal slices, selectively activates Cav2.2 channels, and said activation correlates with increased neurotransmitter release. Furthermore, in vivo perfusion of α-synuclein into the striatum also leads to acute dopamine release. We further demonstrate that α-synuclein reduces the amount of plasma membrane cholesterol and alters the partitioning of Cav2.2 channels, which move from raft to cholesterol-poor areas of the plasma membrane. We provide evidence for a novel mechanism through which α-synuclein acts from the extracellular milieu to modulate neurotransmitter release and propose a unifying hypothesis for the mechanism of α-synuclein action on multiple targets: the reorganization of plasma membrane microdomains.

KW - Dopamine release

KW - Extracellular alpha-synuclein

KW - Lipid rafts

UR - http://www.scopus.com/inward/record.url?scp=84905695099&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0608-14.2014

DO - 10.1523/JNEUROSCI.0608-14.2014

M3 - Article

C2 - 25100594

AN - SCOPUS:84905695099

VL - 34

SP - 10603

EP - 10615

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 32

ER -