Brain : a journal of neurologyOct 29, 2026

E3 ubiquitin ligases: key proteins for protein balance affected in inherited nerve disorders

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Nov 2, 2026

Abstract

Disruption of E3 ubiquitin ligase function is linked to inherited peripheral neuropathies and progressive axonal degeneration.

Inherited peripheral neuropathies are associated with dysfunction of specific E3 ubiquitin ligases, including TRIM2, LRSAM1, UBE3C, and GAN.
These E3 ligases play a critical role in managing protein quality-control pathways essential for maintaining peripheral axon health.
Dysfunction of these proteins leads to impaired protein degradation, autophagy, and stability of the cytoskeleton.
Despite structural and functional differences among the ligases, their dysfunction shares a common impact on protein homeostasis in peripheral axons.
The findings suggest a potential vulnerability of long peripheral axons to disruptions in ubiquitin-mediated protein regulation.

Simplified

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.

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E3 ubiquitin ligases: key proteins for protein balance affected in inherited nerve disorders

Abstract

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