The Integrated UPR and ERAD in Oligodendrocytes Maintain Myelin Thickness in Adults by Regulating Myelin Protein Translation.
Animals
Endoplasmic Reticulum-Associated Degradation
/ physiology
Enzyme Activation
Female
Intracellular Signaling Peptides and Proteins
/ genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myelin Sheath
/ physiology
Oligodendroglia
/ physiology
Protein Biosynthesis
/ physiology
Psychomotor Performance
/ physiology
Ubiquitin-Protein Ligases
/ physiology
Unfolded Protein Response
/ physiology
eIF-2 Kinase
/ physiology
ERAD
PERK
UPR
myelin thickness
oligodendrocyte
protein translation
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
ISSN: 1529-2401
Titre abrégé: J Neurosci
Pays: United States
ID NLM: 8102140
Informations de publication
Date de publication:
21 10 2020
21 10 2020
Historique:
received:
13
03
2020
revised:
09
08
2020
accepted:
10
09
2020
pubmed:
23
9
2020
medline:
2
2
2021
entrez:
22
9
2020
Statut:
ppublish
Résumé
Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Herein, we showed that Sel1L deficiency specifically in oligodendrocytes caused ERAD impairment, the UPR activation, and attenuation of myelin protein biosynthesis; and resulted in late-onset, progressive myelin thinning in the CNS of adult mice (both male and female). The pancreatic ER kinase (PERK) branch of the UPR functions as the master regulator of protein translation in ER-stressed cells. Importantly, PERK inactivation reversed attenuation of myelin protein biosynthesis in oligodendrocytes and restored myelin thickness in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). Conversely, blockage of proteolipid protein production exacerbated myelin thinning in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). These findings suggest that impaired ERAD in oligodendrocytes reduces myelin thickness in the adult CNS through suppression of myelin protein translation by activating PERK.
Identifiants
pubmed: 32958569
pii: JNEUROSCI.0604-20.2020
doi: 10.1523/JNEUROSCI.0604-20.2020
pmc: PMC7577598
doi:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
Sel1h protein, mouse
0
Syvn1 protein, mouse
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
PERK kinase
EC 2.7.11.1
eIF-2 Kinase
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
8214-8232Subventions
Organisme : NINDS NIH HHS
ID : R01 NS094151
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS105689
Pays : United States
Informations de copyright
Copyright © 2020 the authors.
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