Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
Transdisciplinary Research Programs, Niigata University, Niigata, Japan.
Sci Adv. 2024 Jul 26;10(30):eadj9335. doi: 10.1126/sciadv.adj9335.
Mutations in Dystonin (), which encodes cytoskeletal linker proteins, cause hereditary sensory and autonomic neuropathy 6 (HSAN-VI) in humans and the () phenotype in mice; however, the neuronal circuit underlying the HSAN-VI and phenotype is unresolved. 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 by Cre-mediated recombination. Sensory neuron-selective deletion led to motor impairment, degeneration of proprioceptive sensory neurons, and disruption of the sensory-motor circuit. Restoration of 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 mice and that the sensory circuit is a therapeutic target for HSAN-VI.
编码细胞骨架连接蛋白的 dystonin 基因突变会导致人类遗传性感觉和自主神经病 6 型（HSAN-VI）和小鼠的 ()表型；然而，HSAN-VI 和 表型的神经元回路仍未得到解决。 小鼠表现出张力障碍运动，伴有激动剂和拮抗剂肌肉的同时收缩，并伴有出生后致死性。在这里，我们使用基因陷阱系统鉴定了感觉运动回路作为主要的致病神经回路，该系统允许通过 Cre 介导的重组对神经回路进行选择性失活和恢复。感觉神经元选择性的 缺失导致运动障碍、本体感觉神经元变性和感觉运动回路中断。使用 Cre 驱动小鼠或单次注射 Cre 表达的腺相关病毒恢复感觉神经元中的 表达可改善感觉变性并改善异常运动。这些发现表明，感觉运动回路参与了 小鼠的运动障碍，并且感觉回路是治疗 HSAN-VI 的靶点。
