Molecular analysis of axonal-intrinsic and glial-associated co-regulation of axon degeneration

Abstract

Wallerian degeneration is an active program tightly associated with axonal degeneration, required for axonal regeneration and functional recovery after nerve damage. Here we provide a functional molecular foundation for our undertstanding of the complex non-cell autonomous role of glial cells in the regulation of axonal degeneration. To shed light on the complexity of the molecular machinery governing axonal degeneration we employ a multi-model, unbiased, in vivo approach combining morphological assesment and quantitative proteomics with in silico-based higher order functional clustering to genetically uncouple the intrinsic and extrinsic processes governing Wallerian degeneration. Highlighting a pivotal role for glial cells in the early stages fragmenting the axon by a cytokinesis-like process and a cell autonomous stage of axonal disintegration associated to mitochondrial dysfunction.

Axonal Degeneration Is Mediated by Necroptosis Activation

“…The crushed site was marked with graphite powder applied in the forceps, and the wound was closed using surgical clips. The sciatic nerve was intraperitoneally injected with necrostatin-1 (Nec-1; 1.65 mg/kg; Sigma-Aldrich, N9037) or its vehicle (3% DMSO in PBS) before crushing as described by Catenaccio et al (2017).…”

“…During Wallerian degeneration, Schwann and immune cells contribute to axonal degeneration (Catenaccio et al, 2017). To analyze whether necroptosis and mitochondrial fragmentation are involved in axonal degeneration in a cell-autonomous manner, pharmacological treatments with Nec-1 and Mdivi were performed in cultures of sensory neurons from DRGs devoid of glial cells (Villegas et al, 2014).…”

Injured Axons Instruct Schwann Cells to Build Constricting Actin Spheres to Accelerate Axonal Disintegration

“…After lesion, SCs can also form a funnel-shaped actin structure, which has been described to be necessary for the formation and elongation of myelin ovoids (Jung et al, 2011). Myelin ovoids were also suggested to induce axonal fragmentation (Catenaccio et al, 2017). We show here that although funnel-shaped actin does co-localize with degenerated myelin ( Figure 4B, pink arrows), actin spheres do not co-localize with these structures ( Figure 4B, white arrows), indicating that actin spheres formed by SCs upon lesion are distinct from funnel-shaped actin found at myelin ovoids.…”

Cytotoxic Immunity in Peripheral Nerve Injury and Pain

“…Schwann cells collaborate with macrophages to phagocytose degenerated myelin after nerve injury utilizing both Tyro3-Axl-Mer (TAM) receptor-mediated and autophagic mechanisms (Brosius Lutz et al, 2017). Recent evidence suggests that Schwann cells may themselves be early participants in peripheral axon degeneration (Catenaccio et al, 2017), and delaying dedifferentiation of Schwann cells prolongs the survival of axons after crush injury (Catenaccio et al, 2017). The presence of newly discovered Schwann cells adjacent to free nerve endings in the skin are ideally placed to mediate in the dying back of nerve terminals that occurs in multiple peripheral neuropathies (Abdo et al, 2019).…”