Mechanisms of distal axonal degeneration in peripheral neuropathies

Abstract

Peripheral neuropathy is a common complication of a variety of diseases and treatments, including diabetes, cancer chemotherapy, and infectious causes (HIV, hepatitis C, and Campylobacter jejuni). Despite the fundamental difference between these insults, peripheral neuropathy develops as a combination of just six primary mechanisms: altered metabolism, covalent modification, altered organelle function and reactive oxygen species formation, altered intracellular and inflammatory signaling, slowed axonal transport, and altered ion channel dynamics and expression. All of these pathways converge to lead to axon dysfunction and symptoms of neuropathy. The detailed mechanisms of axon degeneration itself have begun to be elucidated with studies of animal models with altered degeneration kinetics, including the slowed Wallerian degeneration (Wlds) and Sarmknockout animal models. These studies have shown axonal degeneration to occur througha programmed pathway of injury signaling and cytoskeletal degradation. Insights into the common disease insults that converge on the axonal degeneration pathway promise to facilitate the development of therapeutics that may be effective against other mechanisms of neurodegeneration.

Hepatitis C virus and neurological damage

“…Clinically, PN manifests itself as motor impairment largely resulting in weakness, sensory defects such as numbness, paresthesia, hyper algesia/allodynia and pain or more severe autonomic dysfunction leading to organ failures. Patients may present with multiple symptoms of varying severity, making it highly heterogeneous, which in turn depends on the underlying trigger [84] . Degeneration of axon, vascular occlusion and inflammation [84] with perivascular trafficking of mononuclear cells are essential pathologic features of the debilitating condition [85] .…”

“…Patients may present with multiple symptoms of varying severity, making it highly heterogeneous, which in turn depends on the underlying trigger [84] . Degeneration of axon, vascular occlusion and inflammation [84] with perivascular trafficking of mononuclear cells are essential pathologic features of the debilitating condition [85] . Demyelization and absence of axonal fascicular differentiation is also reported.…”

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy

“…An array of factors, such as dysfunction of mitochondria and endoplasmic reticulum, hypercholesterolemia, endothelial dysfunction, and ischemia/hypoxia, are considered to play an important role in the development of diabetic neuropathy Cashman & Höke, 2015;Feldman, Nave, Jensen, & Bennett, 2017;Gonçalves et al, 2017). Pathological studies of sural nerve biopsies from patients with diabetic neuropathy typically demonstrate axonal atrophy, demyelination, axonal degeneration with regeneration, and microangiopathy (Biessels et al, 2014;Malik et al, 1989Malik et al, , 2005Thomas et al, 1996).…”

Axon Transport and Neuropathy

“…7e13 Emerging evidence suggests that the effects of many different neuropathy-associated factors may converge on a relatively small number of molecular pathways and processes that are essential for maintaining axon/innervation integrity. 14 Here, I review some of the neuropathy-associated cellular processes that appear to be targets of many diverse disease-causing insults and then focus on axon transport and growth factor signaling as processes that are particularly vulnerable. Finally, by way of example, I discuss a rare group of monogenic congenital PNs, known as hereditary sensory and autonomic neuropathy (HSAN), and review some published and unpublished data, indicating that these phenotypically similar diseases may be caused, at least in part, by genetic mutations that disrupt targetderived signaling and axon transport pathways.…”