UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Pathophysiology of Dyt1-Tor1a dystonia in mice is mediated by spinal neural circuit dysfunction

Pocratsky, Amanda M; Nascimento, Filipe; Özyurt, M Görkem; White, Ian J; Sullivan, Roisin; O'Callaghan, Benjamin J; Smith, Calvin C; ... Brownstone, Robert M; + view all (2023) Pathophysiology of Dyt1-Tor1a dystonia in mice is mediated by spinal neural circuit dysfunction. Science Translational Medicine , 15 (694) , Article eadg3904. 10.1126/scitranslmed.adg3904. Green open access

[thumbnail of Pocratsky et al STM 2023 AAM.pdf]
Preview
Text
Pocratsky et al STM 2023 AAM.pdf - Accepted Version

Download (239MB) | Preview

Abstract

Dystonia, a neurological disorder defined by abnormal postures and disorganized 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 generalized 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 disorganized contractions, including cocontractions of antagonist muscle groups, during voluntary movements. Spontaneous activity, disorganized 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.

Type: Article
Title: Pathophysiology of Dyt1-Tor1a dystonia in mice is mediated by spinal neural circuit dysfunction
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/scitranslmed.adg3904
Publisher version: https://doi.org/10.1126/scitranslmed.adg3904
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Animals, Brain, Dystonia, Dystonia Musculorum Deformans, Humans, Mice, Mice, Knockout, Molecular Chaperones
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10170777
Downloads since deposit
15Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item