E3 ubiquitin ligases: a vital component of proteostasis impaired in hereditary neuropathies

Protein homeostasis is essential for the maintenance of peripheral axons and depends on co-ordinated protein synthesis, folding, ubiquitination and directing protein fate across multiple protein quality-control pathways. E3 ubiquitin ligases are central to this network by conferring substrate specificity and enabling precise spatiotemporal regulation of protein homeostasis. Increasing genetic and functional evidence implicates the disruption of E3 ligase function in inherited peripheral neuropathies, providing a mechanistic link between impaired proteostasis and progressive axonal degeneration. Here, we examine inherited peripheral neuropathies associated with dysfunction of Tripartite Motif-Containing Protein 2 (TRIM2), Leucine Rich Repeat and Sterile Alpha Motif Containing 1 (LRSAM1), Ubiquitin Protein Ligase E3C (UBE3C) and the Cullin-Ring 3 (CUL3) substrate adapter, Gigaxonin (GAN). Although these proteins differ in structure, substrates and disease mechanisms, their dysfunction converges on disruption of proteasomal degradation, autophagy and cytoskeletal homeostasis. By integrating these genetically distinct neuropathies within a common mechanistic framework, we propose this positions E3 ubiquitin ligases as selective regulators of multiple protein quality-control pathways and highlights the specific vulnerability of long peripheral axons to the disruption of ubiquitin-mediated proteostasis.