Publication dans Neurobiolgy of disease pour P3M

Title: Altered action potential waveform and shorter axonal initial segment in hiPSC derived motor neurons with mutations in VRK1

Authors: Rémi Bos, Khalil Rihan, Patrice Quintana, Lara El-Bazzal,
Nathalie Bernard-Marissal, Nathalie Da Silva, Rosette Jabbour,
André Mégarbané, Marc Bartoli, Frédéric Brocard, Valérie
Delague

Short abstract In this study, Bos et al. show that motoneurons (MNs) derived from human induced-pluripotent stem cells (iPSCs) obtained from healthy individuals or patients harbouring VRK1 mutations (Patient II.2) develop similar electrophysiological firing subtypes. However, patient’s hiPSC-MNs display APs of shorter amplitude and larger duration. This modification is likely to result from a decrease in the peak Na⁺ currents accompanied by a decrease in the Ankyrin G-positive axonal initial segment (AIS) length. These data from human MNs indicate that mutations in VRK1 contribute to the alteration of the action potential waveform that may ultimately lead to the upper and motor neuron disease affecting these patients.

Article abstract

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 from patients with VRK1 mutations are functional and sustain typical firing patterns of spinal MNs.
• hiPSC-MNs from patients with VRK1 mutations display smaller action potential and shorter Axonal Initial Segment.
• hiPSC-MNs are a useful platform to study Motor Inherited Peripheral Neuropathies