Speech- and language-linked FOXP2 mutation targets protein motors in striatal neurons.

Autor:	Kuo HY; Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.; Institute of Anatomy and Cell Biology, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan., Chen SY; Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan., Huang RC; Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan., Takahashi H; Department of Neurology, National Hospital Organization, Tottori Medical Center, Tottori 689-0203, Japan., Lee YH; Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan., Pang HY; Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan., Wu CH; Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan., Graybiel AM; McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Liu FC; Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2023 Aug 01; Vol. 146 (8), pp. 3542-3557.
DOI:	10.1093/brain/awad090
Abstrakt:	Human speech and language are among the most complex motor and cognitive abilities. The discovery of a mutation in the transcription factor FOXP2 in KE family members with speech disturbances has been a landmark example of the genetic control of vocal communication in humans. Cellular mechanisms underlying this control have remained unclear. By leveraging FOXP2 mutation/deletion mouse models, we found that the KE family FOXP2R553H mutation directly disables intracellular dynein-dynactin 'protein motors' in the striatum by induction of a disruptive high level of dynactin1 that impairs TrkB endosome trafficking, microtubule dynamics, dendritic outgrowth and electrophysiological activity in striatal neurons alongside vocalization deficits. Dynactin1 knockdown in mice carrying FOXP2R553H mutations rescued these cellular abnormalities and improved vocalization. We suggest that FOXP2 controls vocal circuit formation by regulating protein motor homeostasis in striatal neurons, and that its disruption could contribute to the pathophysiology of FOXP2 mutation/deletion-associated speech disorders. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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