Schwann cell autophagy counteracts the onset and chronification of neuropathic pain

Abstract

Axonal degeneration in peripheral nerves after injury is accompanied by myelin degradation initiated by Schwann cells (SCs). These cells activate autophagy, a ubiquitous cytoprotective process essential for degradation and recycling of cellular constituents. Concomitantly to nerve insult and axonal degeneration, neuropathic pain (NeP) arises. The role of SC autophagy in the mechanisms underlying NeP is still unknown. In this study, we examined the role of the autophagy during the early phase of Wallerian degeneration in NeP induction and chronification by using a murine model of peripheral nerve lesion (chronic constriction injury). We demonstrate that the autophagy inducer rapamycin, administered in the first week after nerve damage, induces long-lasting analgesic and antiinflammatory effects, facilitates nerve regeneration, and prevents pain chronification. Conversely, when autophagy is altered, by means of autophagic inhibitor 3-methyladenine administration or as occurs in activating molecule in Beclin-1-regulated autophagy transgenic mice (Ambra1(+/gt)), NeP is dramatically enhanced and prolonged. Immunohistochemical and ultrastructural evaluations show that rapamycin is able to increase autophagic flux in SCs, to accelerate myelin compaction, and to reduce inflammatory and immune reaction. Proteomic analysis combined with bioinformatic analysis suggests that a redox-sensitive mechanism could be responsible for SC autophagy activation. These data suggest that a deficiency of autophagic activity in SCs can be an early event in the origin of NeP chronification and that autophagy modulation may represent a powerful pharmacological approach to prevent the onset and chronification of NeP in the clinical setting.

Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy

“…Protein waste and aggregates and reactive oxygen species further increase neuronal stress (Tai and Schuman, 2008) and impairment of microglial or Schwann cell autophagy after nerve injury has been suggested to contribute to neuropathic pain (Berliocchi et al, 2011;Marinelli et al, 2014;Shi et al, 2013). Synaptic protein degradation and de novo synthesis are also prerequisites for synapse remodeling (Bingol and Schuman, 2005;Sutton and Schuman, 2006), reestablishment of homeostasis (Wolff et al, 1995) and maintenance of synaptic vesicle numbers, the latter mediated by Rab26, which directly links autophagosomes with synaptic vesicles (Binotti et al, 2015).…”

Ambra1 at a glance

“…Another interesting pathological phenotype observed in these Ambra1 +/gt mice is a dramatically enhanced and prolonged neuropathic pain that occurs following a nerve insult and axonal degeneration (Marinelli et al, 2014). Ambra1 haploinsufficiency, which mimics the reduced autophagic response in Schwann cells after nerve injury, results in a painful response that is so pronounced and persistent that mice display self-lesioning behaviors against the injured limb (Marinelli et al, 2014).…”

“…In the context of pathology, AMBRA1 has, initially, been implicated in impaired embryogenesis and found to be involved in mouse congenital malformation and human neurological disorders (Dere et al, 2014;Fimia et al, 2007;Heinrich et al, 2013, Marinelli et al, 2014Rietschel et al, 2012;Skobo et al, 2014;Vázquez et al, 2012). Beyond this point, AMBRA1 is a bona fide tumor suppressor gene and has been found to be mutated in a significant percentage of human tumors of various tissues (Cianfanelli et al, 2015c).…”

Autophagy in the posterior interosseous nerve of patients with type 1 and type 2 diabetes mellitus: an ultrastructural study

“…Furthermore, in insulin-induced hypoglycaemic rats, autophagy-related structures were observed in degenerating and regenerating axons and their associated Schwann cells [8]. Lack of autophagic activity in Schwann cells has been associated with neuropathic pain in a murine model of peripheral nerve lesion [20].…”