Progressive motor weakness in transgenic mice expressing human TDP-43

被引:154
作者
Stallings, Nancy R. [1 ]
Puttaparthi, Krishna [1 ]
Luther, Christina M. [1 ]
Burns, Dennis K. [2 ]
Elliott, Jeffrey L. [1 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA
关键词
ALS; Motor neuron; Neurodegeneration; TDP-43; Myopathy; Inclusions; AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; DISEASE; MUTATIONS; PROTEIN; AGGREGATION; ALS; OVEREXPRESSION; INCLUSIONS; TOXICITY;
D O I
10.1016/j.nbd.2010.06.017
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Familial ALS patients with TDP-43 gene mutations and sporadic ALS patients share common TDP-43 neuronal pathology. To delineate mechanisms underlying TDP-43 proteinopathies, transgenic mice expressing A315T, M337V or wild type human TDP-43 were generated. Multiple TDP-43 founders developed a severe early motor phenotype that correlated with TDP-43 levels in spinal cord. Three A315T TDP-43 lines developed later onset paralysis with cytoplasmic ubiquitin inclusions, gliosis and TDP-43 redistribution and fragmentation. The WT TDP-43 mouse line with highest spinal cord expression levels remains asymptomatic, although these mice show spinal cord pathology. One WT TDP-43 line with high skeletal muscle levels of TDP-43 developed a severe progressive myopathy. Over-expression of TDP-43 in vivo is sufficient to produce progressive motor phenotypes by a toxic gain of function paradigm. Transgenic mouse lines expressing untagged mutant and wild type TDP-43 under the same promoter represent a powerful new model system for studying TDP-43 proteinopathies in vivo. (c) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:404 / 414
页数:11
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