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The Journal of Neuroscience, December 15, 2001, 21(24):9549-9560
Expression of A53T Mutant But Not Wild-Type  -Synuclein in PC12
Cells Induces Alterations of the Ubiquitin-Dependent Degradation
System, Loss of Dopamine Release, and Autophagic Cell Death
Leonidas
Stefanis1, 2,
Kristin E.
Larsen2,
Hardy
J.
Rideout2,
David
Sulzer2, 3, and
Lloyd A.
Greene1
Departments of 1 Pathology, 2 Neurology,
and 3 Psychiatry, Columbia University, New York, New
York 10032
 -Synuclein mutations have been identified in certain families
with Parkinson's disease (PD), and -synuclein is a major component of Lewy bodies. Other genetic data indicate that the
ubiquitin-dependent proteolytic system is involved in PD pathogenesis.
We have generated stable PC12 cell lines expressing wild-type or A53T
mutant human -synuclein. Lines expressing mutant but not wild-type
-synuclein show: (1) disruption of the ubiquitin-dependent
proteolytic system, manifested by small cytoplasmic ubiquitinated
aggregates and by an increase in polyubiquitinated proteins; (2)
enhanced baseline nonapoptotic death; (3) marked accumulation of
autophagic-vesicular structures; (4) impairment of lysosomal
hydrolysis and proteasomal function; and (5) loss of
catecholamine-secreting dense core granules and an absence of
depolarization-induced dopamine release. Such findings raise the
possibility that the primary abnormality in these cells may involve one
or more deficits in the lysosomal and/or proteasomal degradation
pathways, which in turn lead to loss of dopaminergic capacity and,
ultimately, to death. These cells may serve as a model to study the
effects of aberrant -synuclein on dopaminergic cell function and survival.
Key words:
Parkinson's disease; Lewy body; ubiquitin; autophagy; proteasome; lysosome; dopamine
Copyright © 2001 Society for Neuroscience 0270-6474/01/21249549-12$05.00/0
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106(12):
4900 - 4905.
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|
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J. Biol. Chem.,
August 29, 2008;
283(35):
23542 - 23556.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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283(34):
23179 - 23188.
[Abstract]
[Full Text]
[PDF]
|
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|
|
|
|
|
E. Kyratzi, M. Pavlaki, and L. Stefanis
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Hum. Mol. Genet.,
July 15, 2008;
17(14):
2160 - 2171.
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[PDF]
|
|
|
|
|
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|
Y. Mizuno, N. Hattori, S.-i. Kubo, S. Sato, K. Nishioka, T. Hatano, H. Tomiyama, M. Funayama, Y. Machida, and H. Mochizuki
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Phil Trans R Soc B,
June 27, 2008;
363(1500):
2215 - 2227.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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Cholesterol Accumulation Is Associated with Lysosomal Dysfunction and Autophagic Stress in Npc1 / Mouse Brain
Am. J. Pathol.,
September 1, 2007;
171(3):
962 - 975.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Gonzalez-Polo, M. Niso-Santano, M. A. Ortiz-Ortiz, A. Gomez-Martin, J. M. Moran, L. Garcia-Rubio, J. Francisco-Morcillo, C. Zaragoza, G. Soler, and J. M. Fuentes
Inhibition of Paraquat-Induced Autophagy Accelerates the Apoptotic Cell Death in Neuroblastoma SH-SY5Y Cells
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June 1, 2007;
97(2):
448 - 458.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Toth, P. Simon, A. L. Kovacs, and T. Vellai
Influence of autophagy genes on ion-channel-dependent neuronal degeneration in Caenorhabditis elegans
J. Cell Sci.,
March 15, 2007;
120(6):
1134 - 1141.
[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]
|
|
|
|
|
|
|
D. W. Dickson
Linking Selective Vulnerability to Cell Death Mechanisms in Parkinson's Disease
Am. J. Pathol.,
January 1, 2007;
170(1):
16 - 19.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
E. V. Mosharov, R. G. W. Staal, J. Bove, D. Prou, A. Hananiya, D. Markov, N. Poulsen, K. E. Larsen, C. M. H. Moore, M. D. Troyer, et al.
{alpha}-Synuclein Overexpression Increases Cytosolic Catecholamine Concentration
J. Neurosci.,
September 6, 2006;
26(36):
9304 - 9311.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Cao, J. A. Espinola, E. Fossale, A. C. Massey, A. M. Cuervo, M. E. MacDonald, and S. L. Cotman
Autophagy Is Disrupted in a Knock-in Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis
J. Biol. Chem.,
July 21, 2006;
281(29):
20483 - 20493.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. St. P. McNaught, T. Jackson, R. JnoBaptiste, A. Kapustin, and C. W. Olanow
Proteasomal dysfunction in sporadic Parkinson's disease
Neurology,
May 23, 2006;
66(10_suppl_4):
S37 - S49.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
A. Iwata, J. C. Christianson, M. Bucci, L. M. Ellerby, N. Nukina, L. S. Forno, and R. R. Kopito
Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation
PNAS,
September 13, 2005;
102(37):
13135 - 13140.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. W. Bertoncini, C. O. Fernandez, C. Griesinger, T. M. Jovin, and M. Zweckstetter
Familial Mutants of {alpha}-Synuclein with Increased Neurotoxicity Have a Destabilized Conformation
J. Biol. Chem.,
September 2, 2005;
280(35):
30649 - 30652.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Chen, J. Thorpe, and J. N. Keller
{alpha}-Synuclein Alters Proteasome Function, Protein Synthesis, and Stationary Phase Viability
J. Biol. Chem.,
August 26, 2005;
280(34):
30009 - 30017.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S M Hague, S Klaffke, and O Bandmann
Neurodegenerative disorders: Parkinson's disease and Huntington's disease
J. Neurol. Neurosurg. Psychiatry,
August 1, 2005;
76(8):
1058 - 1063.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. B. Cole, D. D. Murphy, J. Lebowitz, L. Di Noto, R. L. Levine, and R. L. Nussbaum
Metal-catalyzed Oxidation of {alpha}-Synuclein: HELPING TO DEFINE THE RELATIONSHIP BETWEEN OLIGOMERS, PROTOFIBRILS, AND FILAMENTS
J. Biol. Chem.,
March 11, 2005;
280(10):
9678 - 9690.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Stefanis
Caspase-Dependent and -Independent Neuronal Death: Two Distinct Pathways to Neuronal Injury
Neuroscientist,
February 1, 2005;
11(1):
50 - 62.
[Abstract]
[PDF]
|
|
|
|
|
|
|
B. Martin-Clemente, B. Alvarez-Castelao, I. Mayo, A. B. Sierra, V. Diaz, M. Milan, I. Farinas, T. Gomez-Isla, I. Ferrer, and J. G. Castano
{alpha}-Synuclein Expression Levels Do Not Significantly Affect Proteasome Function and Expression in Mice and Stably Transfected PC12 Cell Lines
J. Biol. Chem.,
December 17, 2004;
279(51):
52984 - 52990.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Shintani and D. J. Klionsky
Autophagy in Health and Disease: A Double-Edged Sword
Science,
November 5, 2004;
306(5698):
990 - 995.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. J. Rideout, P. Dietrich, Q. Wang, W. T. Dauer, and L. Stefanis
{alpha}-Synuclein Is Required for the Fibrillar Nature of Ubiquitinated Inclusions Induced by Proteasomal Inhibition in Primary Neurons
J. Biol. Chem.,
November 5, 2004;
279(45):
46915 - 46920.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Cuervo, L. Stefanis, R. Fredenburg, P. T. Lansbury, and D. Sulzer
Impaired Degradation of Mutant {alpha}-Synuclein by Chaperone-Mediated Autophagy
Science,
August 27, 2004;
305(5688):
1292 - 1295.
[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]
|
|
|
|
|
|
|
E. Lindersson, R. Beedholm, P. Hojrup, T. Moos, W. Gai, K. B. Hendil, and P. H. Jensen
Proteasomal Inhibition by {alpha}-Synuclein Filaments and Oligomers
J. Biol. Chem.,
March 26, 2004;
279(13):
12924 - 12934.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-J. Lee, F. Khoshaghideh, S. Patel, and S.-J. Lee
Clearance of {alpha}-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway
J. Neurosci.,
February 25, 2004;
24(8):
1888 - 1896.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-H. Qin, Y. Wang, K. B. Kegel, A. Kazantsev, B. L. Apostol, L. M. Thompson, J. Yoder, N. Aronin, and M. DiFiglia
Autophagy regulates the processing of amino terminal huntingtin fragments
Hum. Mol. Genet.,
December 15, 2003;
12(24):
3231 - 3244.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. F. Outeiro and S. Lindquist
Yeast Cells Provide Insight into Alpha-Synuclein Biology and Pathobiology
Science,
December 5, 2003;
302(5651):
1772 - 1775.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. C. J. Lang-Rollin, H. J. Rideout, M. Noticewala, and L. Stefanis
Mechanisms of Caspase-Independent Neuronal Death: Energy Depletion and Free Radical Generation
J. Neurosci.,
December 3, 2003;
23(35):
11015 - 11025.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Fortun, W. A. Dunn Jr, S. Joy, J. Li, and L. Notterpek
Emerging Role for Autophagy in the Removal of Aggresomes in Schwann Cells
J. Neurosci.,
November 19, 2003;
23(33):
10672 - 10680.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. M. Dawson and V. L. Dawson
Molecular Pathways of Neurodegeneration in Parkinson's Disease
Science,
October 31, 2003;
302(5646):
819 - 822.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Guimaraes, M. Benchimol, G. P. Amarante-Mendes, and R. Linden
Alternative Programs of Cell Death in Developing Retinal Tissue
J. Biol. Chem.,
October 24, 2003;
278(43):
41938 - 41946.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Dong, B. Ferger, J.-C. Paterna, D. Vogel, S. Furler, M. Osinde, J. Feldon, and H. Bueler
Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1
PNAS,
October 14, 2003;
100(21):
12438 - 12443.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Fornai, P. Lenzi, M. Gesi, M. Ferrucci, G. Lazzeri, C. L. Busceti, R. Ruffoli, P. Soldani, S. Ruggieri, M. G. Alessandri, et al.
Fine Structure and Biochemical Mechanisms Underlying Nigrostriatal Inclusions and Cell Death after Proteasome Inhibition
J. Neurosci.,
October 1, 2003;
23(26):
8955 - 8966.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
H. J. Rideout, Q. Wang, D. S. Park, and L. Stefanis
Cyclin-Dependent Kinase Activity Is Required for Apoptotic Death But Not Inclusion Formation in Cortical Neurons after Proteasomal Inhibition
J. Neurosci.,
February 15, 2003;
23(4):
1237 - 1245.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Allen, P. R. Heath, J. Kirby, S. B. Wharton, M. R. Cookson, F. M. Menzies, R. E. Banks, and P. J. Shaw
Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways
J. Biol. Chem.,
February 14, 2003;
278(8):
6371 - 6383.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. J. Ryu, H. P. Harding, J. M. Angelastro, O. V. Vitolo, D. Ron, and L. A. Greene
Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cellular Models of Parkinson's Disease
J. Neurosci.,
December 15, 2002;
22(24):
10690 - 10698.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Lotharius, S. Barg, P. Wiekop, C. Lundberg, H. K. Raymon, and P. Brundin
Effect of Mutant alpha -Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line
J. Biol. Chem.,
October 4, 2002;
277(41):
38884 - 38894.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. G. Perez, J. C. Waymire, E. Lin, J. J. Liu, F. Guo, and M. J. Zigmond
A Role for alpha -Synuclein in the Regulation of Dopamine Biosynthesis
J. Neurosci.,
April 15, 2002;
22(8):
3090 - 3099.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
