HERC1 Ubiquitin Ligase Is Required for Normal Axonal Myelination in the Peripheral Nervous System

  • Sara Bachiller
  • María Angustias Roca-Ceballos
  • Irene García-Domínguez
  • Eva María Pérez-Villegas
  • David Martos-Carmona
  • Miguel Ángel Pérez-Castro
  • Luis Miguel Real
  • José Luis Rosa
  • Lucía Tabares
  • José Luis Venero
  • José Ángel Armengol
  • Ángel Manuel Carrión
  • Rocío Ruiz


A missense mutation in HERC1 provokes loss of cerebellar Purkinje cells, tremor, and unstable gait in tambaleante (tbl) mice. Recently, we have shown that before cerebellar degeneration takes place, the tbl mouse suffers from a reduction in the number of vesicles available for release at the neuromuscular junction (NMJ). The aim of the present work was to study to which extent the alteration in HERC1 may affect other cells in the nervous system and how this may influence the motor dysfunction observed in these mice. The functional analysis showed a consistent delay in the propagation of the action potential in mutant mice in comparison with control littermates. Morphological analyses of glial cells in motor axons revealed signs of compact myelin damage as tomacula and local hypermyelination foci. Moreover, we observed an alteration in non-myelinated terminal Schwann cells at the level of the NMJ. Additionally, we found a significant increment of phosphorylated Akt-2 in the sciatic nerve. Based on these findings, we propose a molecular model that could explain how mutated HERC1 in tbl mice affects the myelination process in the peripheral nervous system. Finally, since the myelin abnormalities found in tbl mice are histological hallmarks of neuropathic periphery diseases, tbl mutant mice could be considered as a new mouse model for this type of diseases.


Inherited peripheral neuropathies Myelin Proteasome Charcot-Marie-tooth Neuromuscular junction 



This work was supported by grants to AMC and RR from the Fundación Ramón Areces—Spain—and DGICYT—Spain (Departamento Gubernamental de Investigaciones Científicas y Tecnológicas: BFU2011-27207); RR [Juan de la Cierva contract JCI-2011-08888 from the Ministerio de Economía y Competitividad (MINECO) and VPPI-US from the University of Seville]; JLV and RRL (MINECO: SAF2015-64171-R); JAA (Spanish Junta de Andalucía BIO-122 and DGICYT BFU2015-64536-R), and SB was supported by the Fundación Ramón Areces fellowships; LMR is the recipient of a grant from the Servicio Andaluz de Salud de la Junta de Andalucía (C-0009-2015). We are grateful to Juan Luis Ribas, Cristina Vaquero, and Asunción Fernández for their helpful technical supports (CITIUS, University of Seville) and to Drs. Manuel Sarmiento and Karin Neukam for their helpful comments and for editorial assistance.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interests.

Supplementary material

12035_2018_1021_Fig9_ESM.gif (700 kb)
Supplementary Figure 1

In transverse sections of the Ranvier node, the aspect of Schwann cells’ microvilli surrounding the nodal membrane (A) (see [41]) was substituted in tbl axons by irregular concentric myelin figs. (B, arrow). Electron microphotographs of transverse sections of tbl sciatic nerve showed: Increased periaxonal space (C, arrow) and anomalous inner mesaxon (D, arrows) together to tomacula of different sizes (E, asterisks). Less affected tbl small and medium size myelinated axons do not show great signs of hypermyelination (H-I) as compared with control axons (F-G) of the same diameter. The number of axons (J) and the percentage (K) per Remak fiber are higher in tbl mice. Scale bars: 5 μm (B), 2 μm (A, E), 1 μm (C, D), 0.5 μm (F, H), and 0.2 μm (G, I). **P < 0.005; ***P < 0.0005. (GIF 700 kb)

12035_2018_1021_MOESM1_ESM.eps (286.3 mb)
High resolution image (EPS 293196 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sara Bachiller
    • 1
  • María Angustias Roca-Ceballos
    • 2
  • Irene García-Domínguez
    • 2
  • Eva María Pérez-Villegas
    • 1
  • David Martos-Carmona
    • 1
  • Miguel Ángel Pérez-Castro
    • 2
  • Luis Miguel Real
    • 3
  • José Luis Rosa
    • 4
  • Lucía Tabares
    • 5
  • José Luis Venero
    • 2
  • José Ángel Armengol
    • 1
  • Ángel Manuel Carrión
    • 1
  • Rocío Ruiz
    • 1
    • 2
  1. 1.Department of Physiology, Anatomy and Cellular BiologyUniversity of Pablo de OlavideSevilleSpain
  2. 2.Department of Biochemistry and Molecular Biology, School of PharmacyUniversity of Seville, and Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSevillaSpain
  3. 3.Unit of Infectious Diseases and MicrobiologyValme University HospitalSevilleSpain
  4. 4.Departament de Ciències Fisiològiques II, IDIBELL, Campus de BellvitgeUniversitat de BarcelonaBarcelonaSpain
  5. 5.Department of Medical Physiology and Biophysics, School of MedicineUniversity of SevilleSevilleSpain

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