Ubiquitin Proteasome System and Microtubules Are Master Regulators of Central and Peripheral Nervous System Axon Degeneration

Abstract

Axonal degeneration is an active process that differs from neuronal death, and it is the hallmark of many disorders affecting the central and peripheral nervous system. Starting from the analyses of Wallerian degeneration, the simplest experimental model, here we describe how the long projecting neuronal populations affected in Parkinson's disease and chemotherapy-induced peripheral neuropathies share commonalities in the mechanisms and molecular players driving the earliest phase of axon degeneration. Indeed, both dopaminergic and sensory neurons are particularly susceptible to alterations of microtubules and axonal transport as well as to dysfunctions of the ubiquitin proteasome system and protein quality control. Finally, we report an updated review on current knowledge of key molecules able to modulate these targets, blocking the on-going axonal degeneration and inducing neuronal regeneration. These molecules might represent good candidates for disease-modifying treatment, which might expand the window of intervention improving patients' quality of life.

Keywords: Parkinson’s disease; axon regeneration; chemotherapy-induced peripheral neuropathies; dying back; microtubules; ubiquitin proteasome system.

Figure 1

Confocal micrograph of cultured neurons, showing a conventional distribution of different tubulin post-translational modifications along the axon (arrowhead) and inside an enlarged terminal (arrow). Tyrosinated tubulin (Tyr TUB, red) is present in the axon and constitutes the microtubule network at the terminal; acetylated tubulin (Ac TUB, green) is enriched along the axon and barely present at the tip; Δ2 tubulin (Δ2 TUB, white) is detectable only in the axon shaft showing a proximal-to-distal distribution. Scale bar = 15 µm.

Figure 2

In healthy neurons (upper panel), ubiquitin-proteasome system is fully active and degrades the unfolded proteins. Not only, the microtubule organization is conventional, as depicted in Figure 1, and sustains the microtubule-dependent functions as the axonal transport of mitochondria or other cargos. In damaged neurons (lower panel), the ubiquitin-proteasome system is blocked, promoting the accumulation of misfolded proteins that induce aggregation, toxicity and axonal degeneration. Microtubule-dependent axonal destruction may be derived from two different conditions: microtubule hyperstabilization, which induces microtubule bundling and block of axonal transport, and microtubule destabilization, with consequent release of microtubule interacting proteins and the dismantling of the railways for intracellular trafficking.