Altered action potential waveform and shorter axonal initial segment in hiPSC-derived motor neurons with mutations in VRK1
Résumé
Summary We recently described new pathogenic variants in VRK1 , in patients affected with distal Hereditary Motor Neuropathy associated with upper motor neurons signs. Specifically, we provided evidences that hiPSC-derived Motor Neurons (hiPSC-MN) from these patients display Cajal bodies (CBs) disassembly and defects in neurite outgrowth and branching. We here focused on the Axonal Initial Segment (AIS) and the related firing properties of hiPSC-MNs from these patients. We found that the patient’s Action Potential (AP) was smaller in amplitude, larger in duration, and displayed a more depolarized threshold while the firing patterns were not altered. These alterations were accompanied by a decrease in the AIS length measured in patients’ hiPSC-MNs. These data indicate that mutations in VRK1 impact the AP waveform and the AIS organization in MNs and may ultimately lead to the related motor neuron disease. Highlights hiPSC-MNs are functional and sustain firing patterns, typical of spinal MNs hiPSC-MNs from patients with VRK1 mutations have altered Action Potential Axonal Initial Segment is shorter in hiPSC-MNs from patients with mutated VRK1 hiPSC-MNs are a useful platform to study Motor Inherited Peripheral Neuropathies eTOC Blurb In human spinal Motor Neurons derived from induced Pluripotent Stem Cells from patients with VRK1 -related distal Hereditary Motor Neuropathy, Bos, Rihan et al. show that the mutations in VRK1 affect the electrical properties of these neurons: they display defects in the initiation of the Action Potential due to a shortening of the Axonal Initial Segment.