Pathophysiology of Dyt1-Tor1a dystonia in mice is mediated by spinal neural circuit dysfunction.
Pathophysiology of Dyt1-Tor1a dystonia in mice is mediated by spinal neural circuit dysfunction.
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DOI：
10.1126/scitranslmed.adg3904
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发表时间：
2023-05-03
影响因子：
17.1
通讯作者：
Brownstone RM
中科院分区：
文献类型：
--
作者：
Pocratsky AM;Nascimento F;Özyurt MG;White IJ;Sullivan R;O'Callaghan BJ;Smith CC;Surana S;Beato M;Brownstone RM
肌张力障碍是一种以异常姿势和无组织运动为特征的神经功能障碍，被认为是一种神经回路障碍，出现在多个大脑区域内和之间。鉴于脊髓神经回路构成了运动控制的最终途径，我们试图确定它们在这种运动障碍中的作用。聚焦于人类最常见的遗传性肌张力障碍形式DYT1-TOR1A，我们在小鼠脊髓和背根神经节(DRG)中产生了Torsin家族1成员A(Tor1a)基因的条件性敲除。我们发现，这些小鼠重现了人类状况的表型，出现了早期发病的全身性扭转肌张力障碍。运动体征早期出现在小鼠的后肢，然后向尾端扩散，影响骨盆、躯干和前肢，整个出生后成熟。从生理上讲，这些小鼠具有肌张力障碍的特征，包括休息时的自发收缩，以及在自愿运动期间过度和无序的收缩，包括拮抗肌群的联合收缩。从这些条件性基因敲除小鼠分离的小鼠脊髓中记录到自发活动、无组织的运动输出和受损的单突触反射，所有这些都是人类肌张力障碍的迹象。单突触反射弧的所有成分都受到影响，包括运动神经元。鉴于将Tor1a条件性基因敲除局限于DRG并没有导致早发性肌张力障碍，我们得出结论，这种肌张力障碍小鼠模型的病理生理基础存在于脊髓神经回路。总之，这些数据为我们目前对肌张力障碍病理生理学的理解提供了新的见解。
Dystonia, a neurological disorder defined by abnormal postures and disorganised movements, is considered to be a neural circuit disorder with dysfunction arising within and between multiple brain regions. Given that spinal neural circuits constitute the final pathway for motor control, we sought to determine their contribution to this movement disorder. Focusing on the most common inherited form of dystonia in humans, DYT1-TOR1A, we generated a conditional knockout of the Torsin Family 1 Member A (Tor1a) gene in the mouse spinal cord and dorsal root ganglia (DRG). We found that these mice recapitulated the phenotype of the human condition, developing early onset generalised torsional dystonia. Motor signs emerged early in the mouse hindlimbs before spreading caudo-rostrally to affect the pelvis, trunk, and forelimbs throughout postnatal maturation. Physiologically, these mice bore the hallmark features of dystonia including spontaneous contractions at rest and excessive and disorganised contractions, including co-contractions of antagonist muscle groups, during voluntary movements. Spontaneous activity, disorganised motor output, and impaired monosynaptic reflexes, all signs of human dystonia, were recorded from isolated mouse spinal cords from these conditional knockout mice. All components of the monosynaptic reflex arc were affected, including motor neurons. Given that confining the Tor1a conditional knockout to DRG did not lead to early onset dystonia, we conclude that the pathophysiological substrate of this mouse model of dystonia lies in spinal neural circuits. Together, these data provide new insights into our current understanding of dystonia pathophysiology.
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DOI：
10.1007/s00702-021-02314-2
发表时间：
2021-04
期刊：
Journal of neural transmission (Vienna, Austria : 1996)
影响因子：
--
作者：
Grütz K;Klein C
通讯作者：
Klein C
影响因子：
2.7
作者：
Yokoi, Fumiaki;Mai Tu Dang;Li, Yuqing
通讯作者：
Li, Yuqing
影响因子：
3.3
作者：
Brownstone RM
通讯作者：
Brownstone RM
影响因子：
8.6
作者：
Albanese, Alberto;Bhatia, Kailash;Bressman, Susan B.;DeLong, Mahlon R.;Fahn, Stanley;Fung, Victor S. C.;Hallett, Mark;Jankovic, Joseph;Jinnah, Hyder A.;Klein, Christine;Lang, Anthony E.;Mink, Jonathan W.;Teller, Jan K.
通讯作者：
Teller, Jan K.
DOI：
10.1073/pnas.0304375101
发表时间：
2004-01-20
影响因子：
11.1
作者：
Goodchild, RE;Dauer, WT
通讯作者：
Dauer, WT