PDF(Pubmed)
Abstract：
Mutations in Dystonin (DST), which encodes cytoskeletal linker proteins, cause hereditary sensory and autonomic neuropathy 6 (HSAN-VI) in humans and the dystonia musculorum (dt) phenotype in mice; however, the neuronal circuit underlying the HSAN-VI and dt phenotype is unresolved. dt mice exhibit dystonic movements accompanied by the simultaneous contraction of agonist and antagonist muscles and postnatal lethality. Here, we identified the sensory-motor circuit as a major causative neural circuit using a gene trap system that enables neural circuit-selective inactivation and restoration of Dst by Cre-mediated recombination. Sensory neuron-selective Dst deletion led to motor impairment, degeneration of proprioceptive sensory neurons, and disruption of the sensory-motor circuit. Restoration of Dst expression in sensory neurons using Cre driver mice or a single postnatal injection of Cre-expressing adeno-associated virus ameliorated sensory degeneration and improved abnormal movements. These findings demonstrate that the sensory-motor circuit is involved in the movement disorders in dt mice and that the sensory circuit is a therapeutic target for HSAN-VI.
摘要：
肌张力素（DST）突变，编码细胞骨架连接蛋白，引起人类的遗传性感觉和自主神经病变6（HSAN-VI）和小鼠的肌张力障碍（dt）表型；然而，HSAN-VI和dt表型的神经元回路尚未解决。dt小鼠表现出肌张力障碍运动，伴随着激动剂和拮抗剂肌肉的同时收缩以及出生后的致死率。这里,我们使用基因捕获系统将感觉运动回路确定为主要的致病神经回路,该系统能够通过Cre介导的重组实现神经回路的选择性失活和Dst的恢复.感觉神经元选择性Dst缺失导致运动障碍，本体感觉神经元的退化，和感觉运动电路的中断。使用Cre驱动小鼠或单次出生后注射表达Cre的腺相关病毒来恢复感觉神经元中的Dst表达改善了感觉变性并改善了异常运动。这些发现表明，感觉-运动回路与dt小鼠的运动障碍有关，并且感觉回路是HSN-VI的治疗靶标。
