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

Abstract

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 α1 in spinal cord motoneurons. Moreover, the activity-targeting drug carbamazepine restores Na/K-ATPase α1 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.

Cytotoxic CD8+T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons

“…It is noteworthy that somatic expression of MHC-I occurred in the presence of IFNγ only in electrically silent neurons (36). Interestingly, the cytotoxicity of mutant CD8 + lymphocytes is observed on electrically immature motoneurons but not on those that after 7 d in vitro become electrically mature as we showed previously (37, 38). Cytotoxic CD8 + T cells could thus contribute to the elimination of nonfunctional motoneurons during the disease.…”

Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs

“…18 The SLC12A6 cotransporter is broadly expressed throughout the brain, spinal cord and peripheral nervous system, amongst other various tissue locations. 16,19 It is inactive under isotonic conditions, but gets activated (by dephosphorylation of its C-terminus) upon cell swelling where it regulates cell volume by the efflux of K + and Clions together with water molecules across the plasma membrane. It is therefore believed to have a key role in cell volume homeostasis and neuronal activity control.…”

Spinal Motoneuron TMEM16F Acts at C-boutons to Modulate Motor Resistance and Contributes to ALS Pathogenesis

“…The 77% of ERRg-negative (ERRg À ) motoneurons include mainly a-motoneurons and 90% of them express TMEM16F ( Figures 2D and 2E). Co-staining with the Na + /K + -ATPase a1 subunit, a plasma membrane marker of motoneurons (Bowerman et al, 2017;Edwards et al, 2013), indicated membrane localization of TMEM16F in motoneurons ( Figure 2F). To further support expression of TMEM16F in motoneurons, we performed costaining with the pre-synaptic marker Synaptophysin.…”