Altered NRG1/ErbB4 signaling and cholesterol metabolism dysregulation are key pathomechanisms in VRK1-related motor neuropathies and motor neuron diseases

Abstract

Hereditary Motor and Sensory Neuropathy (HMSN), or Charcot-Marie-Tooth disease (CMT), are the most common group of Inherited peripheral neuropathies (IPN), characterized by a strong clinical and genetic heterogeneity. Among them, distal Hereditary Motor Neuropathy (dHMN), also known as neuronopathy, is a subgroup, where only motor nerves are affected. This subgroup is also genetically heterogeneous, with 25 genes described to date, of which VRK1, that we have recently described as responsible for dHMN, associated to upper motor neuron signs. There are now more than thirty mutations in VRK1, which cause a range of neurological diseases affecting motor neurons (mainly lower, but also upper) or their axons in the peripheral nervous system, that we design as VRK1-related motor neuron diseases. In two previous studies, we have demonstrated that dHMN due to VRK1 mutations lead to reduced levels of VRK1 in the nucleus, and that this depletion alters the dynamics of coilin, a phosphorylation target of VRK1. hiPSC-derived Motor Neurons (hiPSC-MN) from these patients, display Cajal Bodies (CBs) disassembly and defects in neurite outgrowth and branching, altered Action Potential (AP) waveform and decreased Axonal Initial Segment (AIS) length. In this study, we have further studied the link between the loss of VRK1 function and the defects observed in hiPSC-MNs, by realizing bulk mRNA-Seq sequencing in this in vitro model of the disease. Our results evidenced altered NRG1/ERBB4 signaling, leading to cholesterol metabolism dysregulation and deregulation of genes encoding the glutamate receptors AMPAR and NMDAR, which role in the Axonal Initial Segment and abnormal AP initiation in hiPSC-MNs remains to be investigated.