 |
 Previous Article | Next Article 
The Journal of Neuroscience, December 1, 1998, 18(23):9673-9684
Glutamate Potentiates the Toxicity of Mutant Cu/Zn-Superoxide
Dismutase in Motor Neurons by Postsynaptic Calcium-Dependent
Mechanisms
Josée
Roy1,
Sandra
Minotti1,
Lichun
Dong2,
Denise A.
Figlewicz2, 3, and
Heather D.
Durham1
1 Montreal Neurological Institute and Department of
Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
H3A 2B4, and Departments of 2 Neurology and
3 Neurobiology and Anatomy, University of Rochester,
University of Rochester Medical Center, Rochester, New York 14642
Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene are
responsible for a subset of familial cases of amyotrophic lateral sclerosis. Using a primary culture model, we have demonstrated that normally nontoxic glutamatergic input, particularly via
calcium-permeable AMPA/kainate receptors, is a major factor in the
vulnerability of motor neurons to the toxicity of SOD-1 mutants.
Wild-type and mutant (G41R, G93A, or N139K) human SOD-1 were expressed
in motor neurons of dissociated cultures of murine spinal cord by
intranuclear microinjection of plasmid expression vector. Both a
general antagonist of AMPA/kainate receptors (CNQX) and a specific
antagonist of calcium-permeable AMPA receptors (joro spider toxin)
reduced formation of SOD-1 proteinaceous aggregates and prevented death
of motor neurons expressing SOD-1 mutants. Partial protection was
obtained by treatment with nifedipine, implicating
Ca2+ entry through voltage-gated calcium channels as
well as glutamate receptors in potentiating the toxicity of mutant
SOD-1 in motor neurons. Dramatic neuroprotection was obtained by
coexpressing the calcium-binding protein calbindin-D28k but not by
increasing intracellular glutathione levels or treatment with the free
radical spin trap agent, N-tert-butyl- -phenylnitrone.
Thus, generalized oxidative stress could have contributed in only a
minor way to death of motor neurons expressing the mutant SOD-1. These
studies demonstrated that the toxicity of these mutants is
calcium-dependent and provide direct evidence that calcium entry during
neurotransmission, coupled with deficiency of cytosolic calcium-binding
proteins, is a major factor in the preferential vulnerability of motor
neurons to disease.
Key words:
amyotrophic lateral sclerosis; ALS; superoxide
dismutase-1; neurotoxicity; motor neuron; culture model; excitotoxicity; glutamate receptors; calbindin; calcium-binding
proteins; glutathione; selective vulnerability; oxidative stress
Copyright © 1998 Society for Neuroscience 0270-6474/98/18239673-12$05.00/0
This article has been cited by other articles:
|
|
|
|
 
H. L. Montie, M. S. Cho, L. Holder, Y. Liu, A. S. Tsvetkov, S. Finkbeiner, and D. E. Merry
Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy
Hum. Mol. Genet.,
June 1, 2009;
18(11):
1937 - 1950.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. S. Ilieva, K. Yamanaka, S. Malkmus, O. Kakinohana, T. Yaksh, M. Marsala, and D. W. Cleveland
Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death
PNAS,
August 26, 2008;
105(34):
12599 - 12604.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Vucic, G. A. Nicholson, and M. C. Kiernan
Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis
Brain,
June 1, 2008;
131(6):
1540 - 1550.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Taylor, B. F. Gibbs, E. Kabashi, S. Minotti, H. D. Durham, and J. N. Agar
Tryptophan 32 Potentiates Aggregation and Cytotoxicity of a Copper/Zinc Superoxide Dismutase Mutant Associated with Familial Amyotrophic Lateral Sclerosis
J. Biol. Chem.,
June 1, 2007;
282(22):
16329 - 16335.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. J. Burke, B .J. Traynor, L . Bruijn, R . Conwit, F . Beal, G . O'Neill, S .C. Fagan, and M .E. Cudkowicz
Neuroprotective agents for clinical trials in ALS: A systematic assessment
Neurology,
February 27, 2007;
68(9):
709 - 710.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Mojsilovic-Petrovic, G.-B. Jeong, A. Crocker, A. Arneja, S. David, D. Russell, and R. G. Kalb
Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors
J. Neurosci.,
September 6, 2006;
26(36):
9250 - 9263.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P J Shaw
Molecular and cellular pathways of neurodegeneration in motor neurone disease
J. Neurol. Neurosurg. Psychiatry,
August 1, 2005;
76(8):
1046 - 1057.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. D. Nguyen, T. D'Aigle, G. Gowing, J.-P. Julien, and S. Rivest
Exacerbation of Motor Neuron Disease by Chronic Stimulation of Innate Immunity in a Mouse Model of Amyotrophic Lateral Sclerosis
J. Neurosci.,
February 11, 2004;
24(6):
1340 - 1349.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. D. Ghadge, B. S. Slusher, A. Bodner, M. D. Canto, K. Wozniak, A. G. Thomas, C. Rojas, T. Tsukamoto, P. Majer, R. J. Miller, et al.
Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models
PNAS,
August 5, 2003;
100(16):
9554 - 9559.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Batulan, G. A. Shinder, S. Minotti, B. P. He, M. M. Doroudchi, J. Nalbantoglu, M. J. Strong, and H. D. Durham
High Threshold for Induction of the Stress Response in Motor Neurons Is Associated with Failure to Activate HSF1
J. Neurosci.,
July 2, 2003;
23(13):
5789 - 5798.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Vila, E. F Barrett, and J. N Barrett
Stimulation-induced mitochondrial [Ca2+] elevations in mouse motor terminals: comparison of wild-type with SOD1-G93A
J. Physiol.,
June 15, 2003;
549(3):
719 - 728.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Robertson, M. M. Doroudchi, M. D. Nguyen, H. D. Durham, M. J. Strong, G. Shaw, J.-P. Julien, and W. E. Mushynski
A neurotoxic peripherin splice variant in a mouse model of ALS
J. Cell Biol.,
March 17, 2003;
160(6):
939 - 949.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Lu, S. L. Chan, W. Fu, and M. P. Mattson
The Lipid Peroxidation Product 4-Hydroxynonenal Facilitates Opening of Voltage-dependent Ca2+ Channels in Neurons by Increasing Protein Tyrosine Phosphorylation
J. Biol. Chem.,
June 28, 2002;
277(27):
24368 - 24375.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. W. Orrell and D. A. Figlewicz
Clinical implications of the genetics of ALS and other motor neuron diseases
Neurology,
July 10, 2001;
57(1):
9 - 17.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. K Vanselow and B. U Keller
Calcium dynamics and buffering in oculomotor neurones from mouse that are particularly resistant during amyotrophic lateral sclerosis (ALS)-related motoneurone disease
J. Physiol.,
June 1, 2000;
525(2):
433 - 445.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. S. Meldrum
Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology
J. Nutr.,
April 1, 2000;
130(4):
1007 - 1007.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
J Brownlees, A Yates, N. Bajaj, D Davis, B. Anderton, P. Leigh, C. Shaw, and C. Miller
Phosphorylation of neurofilament heavy chain side-arms by stress activated protein kinase-1b/Jun N-terminal kinase-3
J. Cell Sci.,
January 2, 2000;
113(3):
401 - 407.
[Abstract]
[PDF]
|
|
|
|
|
|
|
S. G. Carriedo, S. L. Sensi, H. Z. Yin, and J. H. Weiss
AMPA Exposures Induce Mitochondrial Ca2+ Overload and ROS Generation in Spinal Motor Neurons In Vitro
J. Neurosci.,
January 1, 2000;
20(1):
240 - 250.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Palecek, M. B Lips, and B. U Keller
Calcium dynamics and buffering in motoneurones of the mouse spinal cord
J. Physiol.,
October 15, 1999;
520(2):
485 - 502.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Blalock, N. M. Porter, and P. W. Landfield
Decreased G-Protein-Mediated Regulation and Shift in Calcium Channel Types with Age in Hippocampal Cultures
J. Neurosci.,
October 1, 1999;
19(19):
8674 - 8684.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. A. Shinder, M.-C. Lacourse, S. Minotti, and H. D. Durham
Mutant Cu/Zn-Superoxide Dismutase Proteins Have Altered Solubility and Interact with Heat Shock/Stress Proteins in Models of Amyotrophic Lateral Sclerosis
J. Biol. Chem.,
April 13, 2001;
276(16):
12791 - 12796.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Millecamps, D. Nicolle, I. Ceballos-Picot, J. Mallet, and M. Barkats
Synaptic sprouting increases the uptake capacities of motoneurons in amyotrophic lateral sclerosis mice
PNAS,
June 19, 2001;
98(13):
7582 - 7587.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Robertson, J.-M. Beaulieu, M. M. Doroudchi, H. D. Durham, J.-P. Julien, and W. E. Mushynski
Apoptotic death of neurons exhibiting peripherin aggregates is mediated by the proinflammatory cytokine tumor necrosis factor-{alpha}
J. Cell Biol.,
October 15, 2001;
155(2):
217 - 226.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
