KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects

NEUROBIOLOGY OF DISEASE

卷:106

Article

Bowerman, Melissa^1,2,3,4  Salsac, Celine¹  Bernard, Veronique^5,6,7  Soulard, Claire^1,2,3  Coque, Emmanuelle^1,2,3  Benlefki, Salim^1,2,3  Hince, Pascale^10,11  Dion, Patrick A.^10,11  Butler-Browne, Gillian^12,13,14  Camu, William^1,15  Bouchard, Jean-Pierre^8,9  Delpire, Eric¹⁶  Rouleau, Guy A.¹⁰  Raoul, Cedric^1,2,3  Scamps, Frederique^1,2,3 

[1] St Eloi Hosp, Inst Neurosci Montpellier, INSERM, UMR1051, 80 Rue Augustin Fliche, F-34091 Montpellier 05, France

[2] Univ Montpellier I, Montpellier, France

[3] Univ Montpellier 2, Montpellier, France

[4] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England

[5] Univ Paris 06, UM CR 18, Paris, France

[6] CNRS, UMR8246, Paris, France

[7] INSERM, U1130, Paris, France

[8] Univ Laval, Quebec City, PQ, Canada

[9] CHU Quebec, Hop Enfant Jesus, Dept Sci Neurolog, Quebec City, PQ, Canada

[10] McGill Univ, Montreal Neurol Inst & Hosp, Dept Neurol & Neurosurg, Montreal, PQ, Canada

[11] Univ Montreal, Dept Pathol & Cellular Biol, Montreal, PQ, Canada

[12] Univ Paris 06, Inst Myol, UM76, Paris, France

[13] INSERM, U974, Paris, France

[14] CNRS, UMR7215, GH Pitie Salpetriere, Paris, France

[15] Gui de Chauliac Hosp, Dept Neurol, ALS Reference Ctr, Montpellier, France

[16] Vanderbilt Univ, Med Ctr, Vanderbilt, MI USA

关键词: Motoneuron;    Andermann syndrome;    Chloride homeostasis;    Electrical activity;    Neuromuscular junction;    Na+/K+ ATPase;   

DOI  :  10.1016/j.nbd.2017.06.013

来源: Elsevier

【 摘 要 】

Loss-of-function mutations in the potassium-chloride cotransporter KCC3 lead to Andermann syndrome, a severe sensorimotor neuropathy characterized by areflexia, amyotrophy and locomotor abnormalities. The molecular events responsible for axonal loss remain poorly understood. Here, we establish that global or neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy that are consistent with the pre-synaptic neurotransmission defects observed in patients. KCC3 depletion does not modify chloride handling, but promotes an abnormal electrical activity among primary motoneurons and mislocalization of Na+/K+ -ATPase alpha 1 in spinal cord motoneurons. Moreover, the activity-targeting drug carbamazepine restores Na+/K+-ATPase alpha 1 localization and reduces NMJ denervation in Slc12a6(-/-) mice. We here propose that abnormal motoneuron electrical activity contributes to the peripheral neuropathy observed in Andermann syndrome. (C) 2017 Elsevier Inc. All rights reserved.

【 授权许可】

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