Common and Divergent Mechanisms in Developmental Neuronal Remodeling and Dying Back Neurodegeneration

Abstract

Cell death is an inherent process that is required for the proper wiring of the nervous system. Studies over the last four decades have shown that, in a parallel developmental pathway, axons and dendrites are eliminated without the death of the neuron. This developmentally regulated 'axonal death' results in neuronal remodeling, which is an essential mechanism to sculpt neuronal networks in both vertebrates and invertebrates. Studies across various organisms have demonstrated that a conserved strategy in the formation of adult neuronal circuitry often involves generating too many connections, most of which are later eliminated with high temporal and spatial resolution. Can neuronal remodeling be regarded as developmentally and spatially regulated neurodegeneration? It has been previously speculated that injury-induced degeneration (Wallerian degeneration) shares some molecular features with 'dying back' neurodegenerative diseases. In this opinion piece, we examine the similarities and differences between the mechanisms regulating neuronal remodeling and those being perturbed in dying back neurodegenerative diseases. We focus primarily on amyotrophic lateral sclerosis and peripheral neuropathies and highlight possible shared pathways and mechanisms. While mechanistic data are only just beginning to emerge, and despite the inherent differences between disease-oriented and developmental processes, we believe that some of the similarities between these developmental and disease-initiated degeneration processes warrant closer collaborations and crosstalk between these different fields.

Figure 1. Axonal elimination during development and dying back neurodegeneration.

A) Restricted axonal fragmentation serves as a key mechanism to prune exuberant connections during development. The axonal fragments are engulfed by glia or epidermal cells. Following pruning, axons often regrow to form new connections in a mechanism that resemble axonal regeneration. B) Genetic lesions or toxic conditions induce axonal loss in a dying back fashion from the target. Dying back is usually accompanied by gliosis and in some cases ends in neuronal cell death.

Figure 2. Major pathways that underlie axonal pruning and dying back neurodegeneration.

Illustration of the main pathways that control developmental axon pruning and axon degeneration by dying back, see text for details. Blue, red and purple text – genes and pathways involved in dying back neurodegeneration (blue), developmental neuronal remodeling (red) or both (purple). MT-Microtubules, Ub-Ubiquitin, UPS-Ubiquitin Proteasome System, TGFβ - Transforming growth factor-β, ESCRT -The endosomal sorting complexes required for transport, Caspases - cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases.