Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS

被引:530
作者
Bosco, Daryl A. [1 ]
Morfini, Gerardo [2 ,7 ]
Karabacak, N. Murat [3 ]
Song, Yuyu [2 ,7 ]
Gros-Louis, Francois [4 ]
Pasinelli, Piera [5 ]
Goolsby, Holly [6 ]
Fontaine, Benjamin A. [1 ]
Lemay, Nathan [1 ]
McKenna-Yasek, Diane [1 ]
Frosch, Matthew P. [6 ]
Agar, Jeffrey N. [3 ]
Julien, Jean-Pierre [4 ]
Brady, Scott T. [2 ,7 ]
Brown, Robert H., Jr. [1 ]
机构
[1] Univ Massachusetts Med Ctr, Dept Neurol, Worcester, MA USA
[2] Univ Illinois, Dept Anat & Cell Biol, Chicago, IL USA
[3] Brandeis Univ, Dept Chem, Waltham, MA 02254 USA
[4] Univ Laval, Dept Psychiat & Neurosci, Res Ctr CHUQ, Quebec City, PQ, Canada
[5] Thomas Jefferson Univ, Farber Inst Neurosci, Weinberg Unit ALS Res, Philadelphia, PA 19107 USA
[6] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA
[7] Marine Biol Lab, Woods Hole, MA 02543 USA
基金
加拿大健康研究院; 美国国家卫生研究院;
关键词
AMYOTROPHIC-LATERAL-SCLEROSIS; FAST AXONAL-TRANSPORT; HUMAN SUPEROXIDE-DISMUTASE; MOTOR-NEURON DISEASE; NEURODEGENERATIVE DISEASES; PROTEIN AGGREGATION; EXTRUDED AXOPLASM; SPINAL-CORDS; LINKED SOD1; MOUSE MODEL;
D O I
10.1038/nn.2660
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild-type SOD1 species was present. Recombinant, oxidized wildtype SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to that of FALS-linked mutant SOD1. Our findings suggest that wild-type SOD1 can be pathogenic in SALS and identify an SOD1-dependent pathogenic mechanism common to FALS and SALS.
引用
收藏
页码:1396 / U133
页数:10
相关论文
共 50 条
[1]   Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation [J].
Abou Ezzi, Samer ;
Urushitani, Makoto ;
Julien, Jean-Pierre .
JOURNAL OF NEUROCHEMISTRY, 2007, 102 (01) :170-178
[2]   Metal-free superoxide dismutase forms soluble oligomers under physiological conditions: A possible general mechanism for familial ALS [J].
Banci, Lucia ;
Bertini, Ivano ;
Durazo, Armando ;
Girotto, Stefania ;
Gralla, Edith Butler ;
Martinelli, Manuele ;
Valentine, Joan Selverstone ;
Vieru, Miguela ;
Whitelegge, Julian P. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (27) :11263-11267
[3]   Superoxide dismutase and the death of motoneurons in ALS [J].
Beckman, JS ;
Estévez, AG ;
Crow, JR .
TRENDS IN NEUROSCIENCES, 2001, 24 (11) :S15-S20
[4]   FAST AXONAL-TRANSPORT IN EXTRUDED AXOPLASM FROM SQUID GIANT-AXON [J].
BRADY, ST ;
LASEK, RJ ;
ALLEN, RD .
SCIENCE, 1982, 218 (4577) :1129-1131
[5]   VIDEO MICROSCOPY OF FAST AXONAL-TRANSPORT IN EXTRUDED AXOPLASM - A NEW MODEL FOR STUDY OF MOLECULAR MECHANISMS [J].
BRADY, ST ;
LASEK, RJ ;
ALLEN, RD .
CELL MOTILITY AND THE CYTOSKELETON, 1985, 5 (02) :81-101
[6]   Do posttranslational modifications of CuZnSOD lead to sporadic amyotrophic lateral sclerosis? [J].
Bredesen, DE ;
Ellerby, LM ;
Hart, PJ ;
WiedauPazos, M ;
Valentine, JS .
ANNALS OF NEUROLOGY, 1997, 42 (02) :135-137
[7]   Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1 [J].
Bruijn, LI ;
Houseweart, MK ;
Kato, S ;
Anderson, KL ;
Anderson, SD ;
Ohama, E ;
Reaume, AG ;
Scott, RW ;
Cleveland, DW .
SCIENCE, 1998, 281 (5384) :1851-1854
[8]  
Chattopadhyay M, 2009, ANTIOXID REDOX SIGN, V11, P1603, DOI [10.1089/ars.2009.2536, 10.1089/ARS.2009.2536]
[9]   DEFECTIVE AXONAL-TRANSPORT IN A TRANSGENIC MOUSE MODEL OF AMYOTROPHIC-LATERAL-SCLEROSIS [J].
COLLARD, JF ;
COTE, F ;
JULIEN, JP .
NATURE, 1995, 375 (6526) :61-64
[10]   Role of axonal transport in neurodegenerative diseases [J].
De Vos, Kurt J. ;
Grierson, Andrew J. ;
Ackerley, Steven ;
Miller, Christopher C. J. .
ANNUAL REVIEW OF NEUROSCIENCE, 2008, 31 :151-173