Mutation-dependent Polymorphism of Cu,Zn-Superoxide Dismutase Aggregates in the Familial Form of Amyotrophic Lateral Sclerosis

被引：86

作者：

Furukawa, Yoshiaki ^{[1
]}

Kaneko, Kumi ^{[1
]}

Yamanaka, Koji ^{[2
]}

Nukina, Nobuyuki ^{[1
]}

机构：

[1] RIKEN Brain Sci Inst, Lab Struct Neuropathol, Wako, Saitama 3510198, Japan

[2] RIKEN Brain Sci Inst, Lab Motor Neuron Dis, Wako, Saitama 3510198, Japan

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2010年 / 285卷 / 29期

关键词：

CU/ZN SUPEROXIDE-DISMUTASE; MOTOR-NEURON DEGENERATION; COPPER-BINDING-SITE; TRANSGENIC MICE; PROTEIN AGGREGATION; HUMAN-DISEASE; CELL-DEATH; SOD1; ALS; SUPEROXIDE-DISMUTASE-1;

D O I：

10.1074/jbc.M110.113597

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：

More than 100 different mutations in Cu, Zn-superoxide dismutase (SOD1) are linked to a familial form of amyotrophic lateral sclerosis (fALS). Pathogenic mutations facilitate fibrillar aggregation of SOD1, upon which significant structural changes of SOD1 have been assumed; in general, however, a structure of protein aggregate remains obscure. Here, we have identified a protease-resistant core in wild-type as well as fALS-causing mutant SOD1 aggregates. Three different regions within an SOD1 sequence are found as building blocks for the formation of an aggregate core, and fALS-causing mutations modulate interactions among these three regions to form a distinct core, namely SOD1 aggregates exhibit mutation-dependent structural polymorphism, which further regulates biochemical properties of aggregates such as solubility. Based upon these results, we propose a new pathomechanism of fALS in which mutation-dependent structural polymorphism of SOD1 aggregates can affect disease phenotypes.

引用

页码：22221 / 22231

页数：11

共 39 条

[11] Truncated wild-type SOD1 and FALS-linked mutant SOD1 cause neural cell death in the chick embryo spinal cord [J].