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

Abstract

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.

The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses

“…(2) anomalous myelination of peripheral nerves and delayed action potential transmission 15 ; (3) increase of autophagy signs in projection neurons of central nervous system as the hippocampal CA3 pyramidal neurons, the neocortical pyramidal neurons, and the motor neurons of the spinal cord 13 ; and, (4) impairment of associative learning linked to absence of LTP and anomalous spinogenesis of the neurons of the lateral amygdala 14 . Therefore, as part of the ubiquitin-proteasome system (UPS) whose alterations have been related with several neurodegenerative diseases of nervous system [28][29][30][31][32][33][34] , all these findings have been explained as the effect of the dysregulation of the autophagy 5,[13][14][15] and/or of the mammalian target of rapamycin complex 1 (mTORC1) altered regulation 5,15 . Present results in hippocampal cultured neurons show that tbl presynaptic terminals possess a noticeable decrease in the number of presynaptic terminals relative to the control ones, which in addition display:…”

“…The animal model of HERC 1 mutation, the tambaleante mouse, was first described as an example of adult cerebellar ataxia by autophagy Purkinje cell death 5 , 9 – 12 . Later studies showed more neurodevelopmental damages to tbl mice phenotype as: (1) delay in synaptic development and maturation of NMJ 16 ; (2) anomalous myelination of peripheral nerves and delayed action potential transmission 15 ; (3) increase of autophagy signs in projection neurons of central nervous system as the hippocampal CA3 pyramidal neurons, the neocortical pyramidal neurons, and the motor neurons of the spinal cord 13 ; and, (4) impairment of associative learning linked to absence of LTP and anomalous spinogenesis of the neurons of the lateral amygdala 14 . Therefore, as part of the ubiquitin–proteasome system (UPS) whose alterations have been related with several neurodegenerative diseases of nervous system 28 – 34 , all these findings have been explained as the effect of the dysregulation of the autophagy 5 , 13 – 15 and/or of the mammalian target of rapamycin complex 1 (mTORC1) altered regulation 5 , 15 .…”

“…Later studies showed more neurodevelopmental damages to tbl mice phenotype as: (1) delay in synaptic development and maturation of NMJ 16 ; (2) anomalous myelination of peripheral nerves and delayed action potential transmission 15 ; (3) increase of autophagy signs in projection neurons of central nervous system as the hippocampal CA3 pyramidal neurons, the neocortical pyramidal neurons, and the motor neurons of the spinal cord 13 ; and, (4) impairment of associative learning linked to absence of LTP and anomalous spinogenesis of the neurons of the lateral amygdala 14 . Therefore, as part of the ubiquitin–proteasome system (UPS) whose alterations have been related with several neurodegenerative diseases of nervous system 28 – 34 , all these findings have been explained as the effect of the dysregulation of the autophagy 5 , 13 – 15 and/or of the mammalian target of rapamycin complex 1 (mTORC1) altered regulation 5 , 15 . Present results in hippocampal cultured neurons show that tbl presynaptic terminals possess a noticeable decrease in the number of presynaptic terminals relative to the control ones, which in addition display: (1) a lower number of the ready releasable and the reserve pools of synaptic vesicles; (2) a shorter zone active; (3) less docked synaptic vesicles; (4) less SYT1; (5) less CLT coated vesicles and CLT immunoreactivity; (6) increased number of big endosomes correlated with and also high expression of EEA1; and, (7) an important presence of autophagosomes.…”

“…The tambaleante ( tbl ) mutant mouse was earliest reported as a model of adult cerebellar ataxia caused by the almost complete autophagy cell death of cerebellar Purkinje cells 9 – 11 . In addition to adult cerebellar Purkinje cell degeneration 5 , 9 – 12 , other alterations in the central and the peripheral nervous system have been recently described in tbl mouse such as: (1) increase of autophagy signs in spinal cord motor neurons and neocortical and CA3 hippocampal pyramidal neurons 13 ; (2) impairment of the associative learning associated to absence of long term potentiation (LTP), altered dendritic spinogenesis, and a drastic decrease of glutamatergic innervation of the lateral amygdala 14 ; (3) anomalous myelination in the sciatic nerve together with alterations of non-myelinating terminal Schwann cells at the neuromuscular junction (NMJ) 15 ; and, (4) altered motor performance owing to a reduction of the motor end-plate area, and impaired evoked neurotransmitter release at the NMJ 16 . Molecular studies identified that HERC1 mutation carried by the tbl mice, and responsible for autophagy cell death, is a Gly483Glu spontaneous substitution located in the N-terminal RCC1 domain (RLD1) 5 .…”

HERCing: Structural and Functional Relevance of the Large HERC Ubiquitin Ligases

“…Herc1 Gly483Glu mutant mice, termed tambaleante , present with delayed growth, short body, high juvenile mortality, and severe ataxia, the latter due to Purkinje cell loss beyond the age of 2 months, correlating with autophagy and decreased mTOR signalling (Mashimo et al, 2009). Tambaleante mice have impaired neurotransmitter release in neuromuscular junctions (Bachiller et al, 2015), defective ubiquitin-proteasome-driven protein aggregate clearance, and increased autophagic flux in neocortical pyramidal, CA3 hippocampal pyramidal and spinal cord motor neurons (Ruiz et al, 2016) and poor myelinisation and delayed action potential transmission (Bachiller et al, 2018). Furthermore, they have impaired associative learning (Perez-Villegas et al, 2018).…”