CSPα reduces aggregates and rescues striatal dopamine release in α-synuclein transgenic mice.
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ABSTRACT:
SUBMITTER: Calo L
PROVIDER: S-EPMC8320296 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
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CSPα reduces aggregates and rescues striatal dopamine release in α-synuclein transgenic mice.
Caló Laura L Hidari Eric E Wegrzynowicz Michal M Dalley Jeffrey W JW Schneider Bernard L BL Podgajna Martyna M Anichtchik Oleg O Carlson Emma E Klenerman David D Spillantini Maria Grazia MG
Brain : a journal of neurology 20210701 6
α-Synuclein aggregation at the synapse is an early event in Parkinson's disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSPα) and α-synuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSPα is a member of the DNAJ/HSP40 family of co-chaperones and like α-synuclein, chaperones the SNARE complex assembly and controls neurotransmitter releas ...[more]
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Project description: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.
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