Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3.
Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3.
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DOI：
10.1093/hmg/ddn422
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Araki, Toshiyuki
中科院分区：
文献类型：
--
作者：
Tateno, Minako;Kato, Shinsuke;Sakurai, Takashi;Nukina, Nobuyuki;Takahashi, Ryosuke;Araki, Toshiyuki
超氧化物歧化酶1 （sod1）基因突变导致家族性肌萎缩性侧索硬化症（FALS），可能是由于错误折叠的突变sod1蛋白的毒性。在这里，我们证明，从FALS发病前开始，错误折叠的SOD1物种与sod1g93a转基因小鼠脊髓腹侧白质中的运动蛋白相关蛋白3 （KAP3）特异性结合。KAP3是一个激酶-2亚基，负责与包括胆碱乙酰转移酶（ChAT）在内的货物结合。SOD1G93A-Tg小鼠的运动轴突也显示出从发病前阶段开始的ChAT转运减少。通过使用NG108-15细胞的新型FALS建模系统，我们发现错误折叠的SOD1物种显著损害了乙酰胆碱的微管依赖性释放。此外，这种损伤能够通过KAP3过表达而正常化。在人类FALS病例中，KAP3也被纳入SOD1聚集物中。这些结果表明，错误折叠的SOD1物种对KAP3的隔离以及由此导致的ChAT转运的抑制在ALS的功能障碍中发挥了作用。
Mutations in the superoxide dismutase 1 (sod1) gene cause familial amyotrophic lateral sclerosis (FALS), likely due to the toxic properties of misfolded mutant SOD1 protein. Here we demonstrated that, starting from the pre-onset stage of FALS, misfolded SOD1 species associates specifically with kinesin-associated protein 3 (KAP3) in the ventral white matter of SOD1G93A-transgenic mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding to cargos including choline acetyltransferase (ChAT). Motor axons in SOD1G93A-Tg mice also showed a reduction in ChAT transport from the pre-onset stage. By employing a novel FALS modeling system using NG108-15 cells, we showed that microtubule-dependent release of acetylcholine was significantly impaired by misfolded SOD1 species. Furthermore, such impairment was able to be normalized by KAP3 overexpression. KAP3 was incorporated into SOD1 aggregates in human FALS cases as well. These results suggest that KAP3 sequestration by misfolded SOD1 species and the resultant inhibition of ChAT transport play a role in the dysfunction of ALS.
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DOI：
10.1002/neu.20230
发表时间：
2006-03-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
Baqri, R;Charan, R;Ray, K
通讯作者：
Ray, K
影响因子：
14.5
作者：
Jonsson, PA;Graffmo, KS;Marklund, SL
通讯作者：
Marklund, SL
影响因子：
6.1
作者：
Dupuis, L;de Tapia, M;Loeffler, JP
通讯作者：
Loeffler, JP
DOI：
10.1016/j.bbrc.2006.02.170
发表时间：
2006-05-12
影响因子：
3.1
作者：
Koyama, S;Arawaka, S;Kato, T
通讯作者：
Kato, T
影响因子：
3.4
作者：
MASELLI, RA;WOLLMAN, RL;ROOS, RP
通讯作者：
ROOS, RP