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The Journal of Neuroscience, October 15, 2002, 22(20):8797-8807
Synaptic Vesicle Depletion Correlates with Attenuated Synaptic
Responses to Prolonged Repetitive Stimulation in Mice Lacking
 -Synuclein
Deborah E.
Cabin1, *,
Kazuhiro
Shimazu3, *,
Diane
Murphy2,
Nelson B.
Cole1,
Wolfram
Gottschalk3,
Kellie L.
McIlwain4, 5,
Bonnie
Orrison1,
Amy
Chen1,
Christopher E.
Ellis1,
Richard
Paylor4,
Bai
Lu3, and
Robert L.
Nussbaum1
1 Genetic Diseases Research Branch and
2 Neurodegeneration Cluster, National Human Genome Research
Institute, Bethesda, Maryland 20892-4472, 3 Laboratory of
Cellular and Synaptic Neurophysiology, National Institute of Child
Health and Human Development, Bethesda, Maryland 20892-4448, 4 Department of Molecular Genetics, Baylor College of
Medicine, Houston, Texas 77030, and 5 Primal, Inc.,
Seattle, Washington 98104
Although the mutation of  -synuclein, a protein associated with
presynaptic vesicles, is implicated in the etiology and pathogenesis of
Parkinson's disease, the biological function of the normal protein is unknown. Mice that lack -synuclein have been generated by
homologous recombination in embryonic stem cells. Electron microscopic
examination of hippocampal synapses revealed a striking selective
deficiency of undocked vesicles without affecting docked vesicles.
Field recording of CA1 synapses in hippocampal slices from the mutant
mice demonstrated normal basal synaptic transmission, paired-pulse
facilitation, and response to a brief train of high-frequency stimulation (100 Hz, 40 pulses) that exhausts only docked vesicles. In
contrast, the -synuclein knock-out mice exhibited significant impairments in synaptic response to a prolonged train of repetitive stimulation (12.5 Hz, 300 pulses) capable of depleting docked as well
as reserve pool vesicles. Moreover, the replenishment of the docked
vesicles by reserve pool vesicles after depletion was slower in the
mutant synapses. Thus, -synuclein may be required for the genesis
and/or maintenance of a subset of presynaptic vesicles, those in the
"reserve" or "resting" pools. These results reveal, for the
first time, the normal function of endogenous -synuclein in
regulating synaptic vesicle mobilization at nerve terminals.
Key words:
-synuclein; genetically engineered mice; docked
synaptic vesicles; reserve pool; readily releasable pool; hippocampus; amphetamine sensitivity
*
D.E.C. and K.S. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/22208797-11$05.00/0
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20(16):
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23(8):
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|
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106(14):
5645 - 5650.
[Abstract]
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|
|
|
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284(11):
7177 - 7189.
[Abstract]
[Full Text]
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|
|
|
|
|
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FASEB J,
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23(2):
329 - 340.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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105(50):
19666 - 19671.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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7(11):
2123 - 2137.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kuwahara, A. Koyama, S. Koyama, S. Yoshina, C.-H. Ren, T. Kato, S. Mitani, and T. Iwatsubo
A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in {alpha}-synuclein transgenic C. elegans
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October 1, 2008;
17(19):
2997 - 3009.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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J Neurophysiol,
August 1, 2008;
100(2):
781 - 795.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Tessari, M. Bisaglia, F. Valle, B. Samori, E. Bergantino, S. Mammi, and L. Bubacco
The Reaction of {alpha}-Synuclein with Tyrosinase: POSSIBLE IMPLICATIONS FOR PARKINSON DISEASE
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283(24):
16808 - 16817.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. P. Bailey, R. E. Nicholls, X.-l. Zhang, Z.-y. Zhou, W. Muller, E. R. Kandel, and P. K. Stanton
G{alpha}i2 inhibition of adenylate cyclase regulates presynaptic activity and unmasks cGMP-dependent long-term depression at Schaffer collateral-CA1 hippocampal synapses
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April 7, 2008;
15(4):
261 - 270.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Soper, S. Roy, A. Stieber, E. Lee, R. B. Wilson, J. Q. Trojanowski, C. G. Burd, and V. M.-Y. Lee
{alpha}-Synuclein-induced Aggregation of Cytoplasmic Vesicles in Saccharomyces cerevisiae
Mol. Biol. Cell,
March 1, 2008;
19(3):
1093 - 1103.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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The Parkinson's disease protein {alpha}-synuclein disrupts cellular Rab homeostasis
PNAS,
January 8, 2008;
105(1):
145 - 150.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. S. Woods, J. M. Boettcher, D. H. Zhou, K. D. Kloepper, K. L. Hartman, D. T. Ladror, Z. Qi, C. M. Rienstra, and J. M. George
Conformation-specific Binding of {alpha}-Synuclein to Novel Protein Partners Detected by Phage Display and NMR Spectroscopy
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November 23, 2007;
282(47):
34555 - 34567.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mackiewicz, K. R. Shockley, M. A. Romer, R. J. Galante, J. E. Zimmerman, N. Naidoo, D. A. Baldwin, S. T. Jensen, G. A. Churchill, and A. I. Pack
Macromolecule biosynthesis: a key function of sleep
Physiol Genomics,
November 14, 2007;
31(3):
441 - 457.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Mandemakers, V. A. Morais, and B. De Strooper
A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases
J. Cell Sci.,
May 15, 2007;
120(10):
1707 - 1716.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Gitler and J. Shorter
Prime Time for {alpha}-Synuclein
J. Neurosci.,
March 7, 2007;
27(10):
2433 - 2434.
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Qin, D. Hu, S. Han, S. H. Reaney, D. A. Di Monte, and A. L. Fink
Effect of 4-Hydroxy-2-nonenal Modification on {alpha}-Synuclein Aggregation
J. Biol. Chem.,
February 23, 2007;
282(8):
5862 - 5870.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. I. Ekstrand, M. Terzioglu, D. Galter, S. Zhu, C. Hofstetter, E. Lindqvist, S. Thams, A. Bergstrand, F. S. Hansson, A. Trifunovic, et al.
Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons
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January 23, 2007;
104(4):
1325 - 1330.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. E. Larsen, Y. Schmitz, M. D. Troyer, E. Mosharov, P. Dietrich, A. Z. Quazi, M. Savalle, V. Nemani, F. A. Chaudhry, R. H. Edwards, et al.
{alpha}-Synuclein Overexpression in PC12 and Chromaffin Cells Impairs Catecholamine Release by Interfering with a Late Step in Exocytosis.
J. Neurosci.,
November 15, 2006;
26(46):
11915 - 11922.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Vigneswara, J. D. Lowenson, C. D. Powell, M. Thakur, K. Bailey, S. Clarke, D. E. Ray, and W. G. Carter
Proteomic Identification of Novel Substrates of a Protein Isoaspartyl Methyltransferase Repair Enzyme
J. Biol. Chem.,
October 27, 2006;
281(43):
32619 - 32629.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Kontopoulos, J. D. Parvin, and M. B. Feany
{alpha}-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity
Hum. Mol. Genet.,
October 15, 2006;
15(20):
3012 - 3023.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Austin, A. M. Floden, E. J. Murphy, and C. K. Combs
{alpha}-Synuclein Expression Modulates Microglial Activation Phenotype
J. Neurosci.,
October 11, 2006;
26(41):
10558 - 10563.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Mazzulli, A. J. Mishizen, B. I. Giasson, D. R. Lynch, S. A. Thomas, A. Nakashima, T. Nagatsu, A. Ota, and H. Ischiropoulos
Cytosolic Catechols Inhibit {alpha}-Synuclein Aggregation and Facilitate the Formation of Intracellular Soluble Oligomeric Intermediates
J. Neurosci.,
September 27, 2006;
26(39):
10068 - 10078.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Leng and D.-M. Chuang
Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity.
J. Neurosci.,
July 12, 2006;
26(28):
7502 - 7512.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Shimazu, M. Zhao, K. Sakata, S. Akbarian, B. Bates, R. Jaenisch, and B. Lu
NT-3 facilitates hippocampal plasticity and learning and memory by regulating neurogenesis
Learn. Mem.,
May 1, 2006;
13(3):
307 - 315.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Kamp and K. Beyer
Binding of {alpha}-Synuclein Affects the Lipid Packing in Bilayers of Small Vesicles
J. Biol. Chem.,
April 7, 2006;
281(14):
9251 - 9259.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. S. Ulmer and A. Bax
Comparison of Structure and Dynamics of Micelle-bound Human {alpha}-Synuclein and Parkinson Disease Variants
J. Biol. Chem.,
December 30, 2005;
280(52):
43179 - 43187.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. W. Smith, H. Jiang, Z. Pei, Y. Tanaka, H. Morita, A. Sawa, V. L. Dawson, T. M. Dawson, and C. A. Ross
Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity
Hum. Mol. Genet.,
December 15, 2005;
14(24):
3801 - 3811.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Fortin, V. M. Nemani, S. M. Voglmaier, M. D. Anthony, T. A. Ryan, and R. H. Edwards
Neural Activity Controls the Synaptic Accumulation of {alpha}-Synuclein
J. Neurosci.,
November 23, 2005;
25(47):
10913 - 10921.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. E. Ellis, E. J. Murphy, D. C. Mitchell, M. Y. Golovko, F. Scaglia, G. C. Barcelo-Coblijn, and R. L. Nussbaum
Mitochondrial Lipid Abnormality and Electron Transport Chain Impairment in Mice Lacking {alpha}-Synuclein
Mol. Cell. Biol.,
November 15, 2005;
25(22):
10190 - 10201.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Utton, W. J. Noble, J. E. Hill, B. H. Anderton, and D. P. Hanger
Molecular motors implicated in the axonal transport of tau and {alpha}-synuclein
J. Cell Sci.,
October 15, 2005;
118(20):
4645 - 4654.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-i. Kubo, V. M. Nemani, R. J. Chalkley, M. D. Anthony, N. Hattori, Y. Mizuno, R. H. Edwards, and D. L. Fortin
A Combinatorial Code for the Interaction of {alpha}-Synuclein with Membranes
J. Biol. Chem.,
September 9, 2005;
280(36):
31664 - 31672.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-J. Lee, S. Patel, and S.-J. Lee
Intravesicular Localization and Exocytosis of {alpha}-Synuclein and its Aggregates
J. Neurosci.,
June 22, 2005;
25(25):
6016 - 6024.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. H. Norris, B. I. Giasson, R. Hodara, S. Xu, J. Q. Trojanowski, H. Ischiropoulos, and V. M.-Y. Lee
Reversible Inhibition of {alpha}-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations
J. Biol. Chem.,
June 3, 2005;
280(22):
21212 - 21219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Dixon, N. Mathias, R. M. Zweig, D. A. Davis, and D. S. Gross
{alpha}-Synuclein Targets the Plasma Membrane via the Secretory Pathway and Induces Toxicity in Yeast
Genetics,
May 1, 2005;
170(1):
47 - 59.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. W. Doss-Pepe, L. Chen, and K. Madura
{alpha}-Synuclein and Parkin Contribute to the Assembly of Ubiquitin Lysine 63-linked Multiubiquitin Chains
J. Biol. Chem.,
April 29, 2005;
280(17):
16619 - 16624.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Cao, C. C. Gelwix, K. A. Caldwell, and G. A. Caldwell
Torsin-Mediated Protection from Cellular Stress in the Dopaminergic Neurons of Caenorhabditis elegans
J. Neurosci.,
April 13, 2005;
25(15):
3801 - 3812.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Greenbaum, C. L. Graves, A. J. Mishizen-Eberz, M. A. Lupoli, D. R. Lynch, S. W. Englander, P. H. Axelsen, and B. I. Giasson
The E46K Mutation in {alpha}-Synuclein Increases Amyloid Fibril Formation
J. Biol. Chem.,
March 4, 2005;
280(9):
7800 - 7807.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Yavich, H. Tanila, S. Vepsalainen, and P. Jakala
Role of {alpha}-Synuclein in Presynaptic Dopamine Recruitment
J. Neurosci.,
December 8, 2004;
24(49):
11165 - 11170.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Chandra, F. Fornai, H.-B. Kwon, U. Yazdani, D. Atasoy, X. Liu, R. E. Hammer, G. Battaglia, D. C. German, P. E. Castillo, et al.
Double-knockout mice for {alpha}- and {beta}-synucleins: Effect on synaptic functions
PNAS,
October 12, 2004;
101(41):
14966 - 14971.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Eisenhofer, I. J. Kopin, and D. S. Goldstein
Catecholamine Metabolism: A Contemporary View with Implications for Physiology and Medicine
Pharmacol. Rev.,
September 1, 2004;
56(3):
331 - 349.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Fortin, M. D. Troyer, K. Nakamura, S.-i. Kubo, M. D. Anthony, and R. H. Edwards
Lipid Rafts Mediate the Synaptic Localization of {alpha}-Synuclein
J. Neurosci.,
July 28, 2004;
24(30):
6715 - 6723.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. C. Jao, A. Der-Sarkissian, J. Chen, and R. Langen
From The Cover: Structure of membrane-bound {alpha}-synuclein studied by site-directed spin labeling
PNAS,
June 1, 2004;
101(22):
8331 - 8336.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Nuscher, F. Kamp, T. Mehnert, S. Odoy, C. Haass, P. J. Kahle, and K. Beyer
{alpha}-Synuclein Has a High Affinity for Packing Defects in a Bilayer Membrane: A THERMODYNAMICS STUDY
J. Biol. Chem.,
May 21, 2004;
279(21):
21966 - 21975.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Wilson, D. D. Murphy, B. I. Giasson, B. Zhang, J. Q. Trojanowski, and V. M.-Y. Lee
Degradative organelles containing mislocalized {alpha}- and {beta}-synuclein proliferate in presenilin-1 null neurons
J. Cell Biol.,
May 10, 2004;
165(3):
335 - 346.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. SIDHU, C. WERSINGER, and P. VERNIER
Does {alpha}-synuclein modulate dopaminergic synaptic content and tone at the synapse?
FASEB J,
April 1, 2004;
18(6):
637 - 647.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Baptista, M. R. Cookson, and D. W. Miller
Parkin and {alpha}-Synuclein: Opponent Actions in The Pathogenesis of Parkinson'S Disease
Neuroscientist,
February 1, 2004;
10(1):
63 - 72.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R. Sharon, I. Bar-Joseph, G. E. Mirick, C. N. Serhan, and D. J. Selkoe
Altered Fatty Acid Composition of Dopaminergic Neurons Expressing {alpha}-Synuclein and Human Brains with {alpha}-Synucleinopathies
J. Biol. Chem.,
December 12, 2003;
278(50):
49874 - 49881.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Ninkina, K. Papachroni, D. C. Robertson, O. Schmidt, L. Delaney, F. O'Neill, F. Court, A. Rosenthal, S. M. Fleetwood-Walker, A. M. Davies, et al.
Neurons Expressing the Highest Levels of {gamma}-Synuclein Are Unaffected by Targeted Inactivation of the Gene
Mol. Cell. Biol.,
November 15, 2003;
23(22):
8233 - 8245.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-M. Itier, P. Ibanez, M. A. Mena, N. Abbas, C. Cohen-Salmon, G. A. Bohme, M. Laville, J. Pratt, O. Corti, L. Pradier, et al.
Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse
Hum. Mol. Genet.,
September 15, 2003;
12(18):
2277 - 2291.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Cousin, C. S. Malladi, T. C. Tan, C. R. Raymond, K. J. Smillie, and P. J. Robinson
Synapsin I-associated Phosphatidylinositol 3-Kinase Mediates Synaptic Vesicle Delivery to the Readily Releasable Pool
J. Biol. Chem.,
August 1, 2003;
278(31):
29065 - 29071.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Webb, B. Ravikumar, J. Atkins, J. N. Skepper, and D. C. Rubinsztein
{alpha}-Synuclein Is Degraded by Both Autophagy and the Proteasome
J. Biol. Chem.,
June 27, 2003;
278(27):
25009 - 25013.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. I. Giasson, M. S. Forman, M. Higuchi, L. I. Golbe, C. L. Graves, P. T. Kotzbauer, J. Q. Trojanowski, and V. M.-Y. Lee
Initiation and Synergistic Fibrillization of Tau and Alpha-Synuclein
Science,
April 25, 2003;
300(5619):
636 - 640.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
