Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination

Abstract
Data availability
Article and author information
Metrics

Abstract

Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

Gustavo Della Flora Nunes

Departments of Biochemistry, SUNY Buffalo, Buffalo, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9323-3556
Emma R Wilson

Departments of Biochemistry, SUNY Buffalo, Buffalo, United States

For correspondence
ewilson5@buffalo.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8069-0173
Edward Hurley

Departments of Biochemistry and Neurology, SUNY Buffalo, Buffalo, United States

For correspondence
edwardhu@buffalo.edu

Competing interests
The authors declare that no competing interests exist.
Bin He

Immunobiology & Transplant Science Center and Department of Surgery,, Houston Methodist Hospital, Houston, TX, 77030, United States

Competing interests
The authors declare that no competing interests exist.
Bert W O'Malley

Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States

For correspondence
berto@bcm.edu

Competing interests
The authors declare that no competing interests exist.
Yannick Poitelon

Dept of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, United States

For correspondence
poitely@amc.edu

Competing interests
The authors declare that no competing interests exist.
Lawrence Wrabetz

Neurology, SUNY Buffalo, Buffalo, United States

For correspondence
lwrabetz@buffalo.edu

Competing interests
The authors declare that no competing interests exist.
M Laura Feltri

Departments of Biochemistry and Neurology, SUNY Buffalo, Buffalo, United States

For correspondence
mlfeltri@buffalo.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2276-9182

Funding

National Institute of Neurological Disorders and Stroke (R01NS100464)

M Laura Feltri

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures have been approved by the Institutional Animal Care and Use Committee (IACUC) of the Roswell Park Cancer Institute (Buffalo-NY, USA), and followed the guidelines stablished by the NIH's Guide for the Care and Use of Laboratory Animals and the regulations in place at the University at Buffalo (Buffalo-NY, USA).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.