α-Synuclein Cooperates with CSPα in Preventing Neurodegeneration

@article{Chandra2005SynucleinCW,
  title={$\alpha$-Synuclein Cooperates with CSP$\alpha$ in Preventing Neurodegeneration},
  author={Sreeganga S. Chandra and Gilbert Gallardo and Rafael Fern{\'a}ndez-Chac{\'o}n and Oliver M. Schl{\"u}ter and Thomas C. S{\"u}dhof},
  journal={Cell},
  year={2005},
  volume={123},
  pages={383-396}
}

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References

SHOWING 1-10 OF 69 REFERENCES
Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions.
TLDR
The results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.
Lipid Rafts Mediate the Synaptic Localization of α-Synuclein
TLDR
It is found that both the A30P mutation and raft disruption redistribute α-synuclein away from synapses, indicating an important role for raft association in the normal function of α- synuclein and its role in the pathogenesis of PD.
Defective membrane interactions of familial Parkinson's disease mutant A30P α-synuclein
TLDR
It is demonstrated that the familial Parkinson’s disease-linked A30P mutant α-Syn is defective in binding to phospholipid vesicles in vitro as determined by vesicle ultracentrifugation, circular dichroism spectroscopy, and low-angle X-ray diffraction, which suggests that this species could be a physiologically relevant and functional entity.
Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System
Interaction of Human α-Synuclein and Parkinson's Disease Variants with Phospholipids
TLDR
It is shown that the capacity to bind lipids is broadly distributed across exons 3, 4, and 5 (encoding residues 1–102), consistent with the hypothesis that α-synuclein's normal functions depend on an ability to undergo a large conformational change in the presence of specific phospholipids.
Lipid Droplet Binding and Oligomerization Properties of the Parkinson's Disease Protein α-Synuclein*
TLDR
Chemical cross-linking demonstrated that synuclein formed small oligomers within cells, primarily dimers and trimers, that preferentially associated with lipid droplets and cell membranes, suggesting that the initial phases ofsynuclein aggregation may occur on the surfaces of membranes.
Alpha-synuclein: normal function and role in neurodegenerative diseases.
Binding of α-Synuclein to Brain Vesicles Is Abolished by Familial Parkinson’s Disease Mutation*
TLDR
It is demonstrated in the rat optic system that a portion of α-synuclein is carried by the vesicle-moving fast component of axonal transport and that it binds to rat brain vesicles through its amino-terminal repeat region and it is proposed that mutant α- synuclein may accumulate, leading to assembly into Lewy body filaments.
The Synaptic Vesicle Protein CSPα Prevents Presynaptic Degeneration
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