| Project/Area Number |
17590870
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Neurology
|
|---|
| Research Institution | Nagoya University |
|---|
Principal Investigator |
NIWA Jun-ichi Nagoya University, Graduate School of Medicine, COE Research, 大学院医学系研究科, COE研究員 (50378022)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SOBUE Gen Nagoya University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (20148315)
|
|---|
| Project Period (FY) |
2005 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2005: ¥2,700,000 (Direct Cost: ¥2,700,000)
|
|---|
| Keywords | Amyotrophic lateral sclerosis / mutant SOD1 / motor neuron / neurodegeneration / Dorfin / disulfide bond / ユビキチンリガーゼ / プロテアソーム / オリゴマー |
|---|
| Research Abstract |
Mutation in ubiquitously expressed copper/zinc superoxide dismutase (SOD1) causes familial amyotrophic lateral sclerosis (FALS), but the mechanism of selective toxicity to motor neurons remains unknown. In FALS patients and mutant SOD1-transgenic (Tg) mice, mutant SOD1 accumulates progressively and forms high molecular weight protein complex only in the affected neural tissues. Dorfin is a RING-type ubiquitin (Ub) ligase and specifically recognizes and ubiquitylates mutant SOD1. We show that Dorfin immunoreactive protein aggregates were observed only in the affected lesion of G93A mutant SOD1-Tg mice and increased dramatically during the clinical course parallel to Ub and SOD1. Dorfin preferentially recognizes and binds with mutant SOD1 derived from the affected tissues and the amount of Dorfin-bound mutant SOD1 increased during the disease course. This lesion-specific Dorfin and mutant SOD1 interaction was remarkably associated with the occurrence of oligomeric SOD1 complex and unusual SOD1 species between the monomer and dimer sizes. These observations were reproduced in the culture cells when the cells were neurally differentiated. These findings suggest that Dorfin is a useful tool for detecting the misfolded mutant SOD1 responsible for selective toxicity to motor neurons. Furthermore, we found that the disulfide bond of mutant SOD1 protein influenced on high molecualr weight aggregates formation and neurotoxicity. Dorfin recognized these intermolecular disulfide-linked mutant SOD1, ubiqutylated and targeted them to the proteasomal degradation.
|
