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 (Wld(S)) and Sarm knockout animal models. These studies have shown axonal degeneration to occur through a 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.

Keywords: Campylobacter jejuni; Chemotherapy induced peripheral neuropathy; Diabetes; Guillain–Barré syndrome; HIV neuropathy; Mechanisms of neuropathy; Mitochondrial aging; Peripheral neuropathy; Post-infectious neuropathy; Wld(S).

Figure 1. Summary of metabolic pathways

A variety of metabolic processes that branch off of glycolysis are dysregulated in diabetes, including the polyol, pentose phosphate, and hexosamine pathways. This dysregulation leads to protein modification, changes in extra- and intracellular signaling (effectors in blue text), and decreased antioxidant capacity secondary to reduced NADPH levels (shown in green). Red arrow indicates inhibition of the pentose phosphate pathway by elevated glucose levels.

Figure 2. Summary of the mechanisms of peripheral nerve degeneration

Peripheral neuropathy in a wide range of disease, including diabetes, CIPN, viral infections, and GBS, develops as a result of the interaction of various combinations of just six processes: altered metabolism, covalent modification, impaired organelle function with ROS/RNS, altered signaling, slowed axonal transport, and altered ion channel dynamics. The figure delineates which process is active in which disease by color, as shown in the key. All of these processes interact to ultimately converge on the neuronal death and/or axonal degeneration pathways, with the major interactions outlined in the above figure. The different black, dark gray, and light gray coloring of the arrows is for clarity only.