Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.
Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.
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DOI：
10.1007/s00401-017-1698-6
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发表时间：
2017-06
影响因子：
12.7
通讯作者：
Da Cruz S
中科院分区：
文献类型：
--
作者：
Ditsworth D;Maldonado M;McAlonis-Downes M;Sun S;Seelman A;Drenner K;Arnold E;Ling SC;Pizzo D;Ravits J;Cleveland DW;Da Cruz S
TDP-43的突变导致肌萎缩性侧索硬化症（ALS），这是一种以运动神经元变性和过早死亡为特征的致命麻痹性疾病。通过表达一种引起als的TDP-43突变体（Q331K）的条件等位基因的小鼠，评估了突变体TDP-43介导的运动神经元损伤的作用，该突变体在整个中枢神经系统的广泛表达模拟了内源性TDP-43。TDP-43Q331K小鼠由于运动神经元的退化和死亡而产生年龄依赖性和突变依赖性运动缺陷。从运动神经元中通过cre重组酶介导的TDP-43Q331K基因切除被证明可以延迟运动症状的发生和tdp -43介导的异常核形态的出现，并消除随后的运动神经元死亡。然而，在运动神经元中选择性地减少突变体TDP-43并不能防止轴突的年龄依赖性变性和神经肌肉连接处的损失，也不能减轻星形胶质细胞增生或小胶质细胞增生。因此，疾病机制是非细胞自主的，在运动神经元中表达的突变体TDP-43决定了疾病的发生，但在其他细胞类型中作用的突变体决定了疾病的进展。本文的在线版本（doi:10.1007/s00401-017-1698-6）包含补充材料，可供授权用户使用。
Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types. The online version of this article (doi:10.1007/s00401-017-1698-6) contains supplementary material, which is available to authorized users.