Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity

被引:157
作者
Niwa, J
Ishigaki, S
Hishikawa, N
Yamamoto, M
Doyu, M
Murata, S
Tanaka, K
Taniguchi, N
Sobue, G
机构
[1] Nagoya Univ, Grad Sch Med, Dept Neurol, Showa Ku, Nagoya, Aichi 4668550, Japan
[2] Tokyo Metropolitan Inst Med Sci, Dept Mol Oncol, Bunkyo Ku, Tokyo 1138613, Japan
[3] Osaka Univ, Grad Sch Med, Dept Biochem, Suita, Osaka 5650871, Japan
关键词
D O I
10.1074/jbc.M206559200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder resulting from the degeneration of motor neurons in the cerebral cortex, brainstem, and spinal cord. The cytopathological hallmark in the remaining motor neurons of ALS is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. In this paper we report that Dorfin, a RING finger-type E3 ubiquitin ligase, is predominantly localized in the inclusion bodies of familial ALS with a copper/zinc superoxide dismutase (SOD1) mutation as well as sporadic AILS. Dorfin physically bound and ubiquitylated various SOD1 mutants derived from familial AILS patients and enhanced their degradation, but it had no effect on the stability of the wild-type SOD1. The overexpression of Dorfin protected against the toxic effects of mutant SOD1 on neural cells and reduced SOD1 inclusions. Our results indicate that Dorfin protects neurons by recognizing and then ubiquitylating mutant SOD1 proteins followed by targeting them for proteasomal degradation.
引用
收藏
页码:36793 / 36798
页数:6
相关论文
共 45 条
[1]   Features of the Parkin/ariadne-like ubiquitin ligase, HHARI, that regulate its interaction with the ubiquitin-conjugating enzyme, UbcH7 [J].
Ardley, HC ;
Tan, NGS ;
Rose, SA ;
Markham, AF ;
Robinson, PA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (22) :19640-19647
[2]   Impairment of the ubiquitin-proteasome system by protein aggregation [J].
Bence, NF ;
Sampat, RM ;
Kopito, RR .
SCIENCE, 2001, 292 (5521) :1552-1555
[3]   SUPEROXIDE-DISMUTASE-1 WITH MUTATIONS LINKED TO FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS POSSESSES SIGNIFICANT ACTIVITY [J].
BORCHELT, DR ;
LEE, MK ;
SLUNT, HS ;
GUARNIERI, M ;
XU, ZS ;
WONG, PC ;
BROWN, RH ;
PRICE, DL ;
SISODIA, SS ;
CLEVELAND, DW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (17) :8292-8296
[4]   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
[5]   ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions [J].
Bruijn, LI ;
Becher, MW ;
Lee, MK ;
Anderson, KL ;
Jenkins, NA ;
Copeland, NG ;
Sisodia, SS ;
Rothstein, JD ;
Borchelt, DR ;
Price, DL ;
Cleveland, DW .
NEURON, 1997, 18 (02) :327-338
[6]   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
[7]   Parkin ubiquitinates the α-synuclein-interacting protein, synphilin-1:: implications for Lewy-body formation in Parkinson disease [J].
Chung, KKK ;
Zhang, Y ;
Lim, KL ;
Tanaka, Y ;
Huang, H ;
Gao, J ;
Ross, CA ;
Dawson, VL ;
Dawson, TM .
NATURE MEDICINE, 2001, 7 (10) :1144-1150
[8]   From Charcot to Lou Gehrig: Deciphering selective motor neuron death in ALS [J].
Cleveland, DW ;
Rothstein, JD .
NATURE REVIEWS NEUROSCIENCE, 2001, 2 (11) :806-819
[9]   SCF and cullin/RING H2-based ubiquitin ligases [J].
Deshaies, RJ .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 1999, 15 :435-467
[10]   Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS [J].
Durham, HD ;
Roy, J ;
Dong, L ;
Figlewicz, DA .
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 1997, 56 (05) :523-530