Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination
- SUNY Buffalo, United States
- Houston Methodist Hospital, United States
- Baylor College of Medicine, United States
- Albany Medical College, United States
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
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
© 2021, Della Flora Nunes et al.
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.
Metrics
-
- 1,554
- views
-
- 265
- downloads
-
- 16
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination
eLife 10:e66278.
https://doi.org/10.7554/eLife.66278
Further reading
-
- Neuroscience
Phantom perceptions like tinnitus occur without any identifiable environmental or bodily source. The mechanisms and key drivers behind tinnitus are poorly understood. The dominant framework, suggesting that tinnitus results from neural hyperactivity in the auditory pathway following hearing damage, has been difficult to investigate in humans and has reached explanatory limits. As a result, researchers have tried to explain perceptual and potential neural aberrations in tinnitus within a more parsimonious predictive-coding framework. In two independent magnetoencephalography studies, participants passively listened to sequences of pure tones with varying levels of regularity (i.e. predictability) ranging from random to ordered. Aside from being a replication of the first study, the pre-registered second study, including 80 participants, ensured rigorous matching of hearing status, as well as age, sex, and hearing loss, between individuals with and without tinnitus. Despite some changes in the details of the paradigm, both studies equivalently reveal a group difference in neural representation, based on multivariate pattern analysis, of upcoming stimuli before their onset. These data strongly suggest that individuals with tinnitus engage anticipatory auditory predictions differently to controls. While the observation of different predictive processes is robust and replicable, the precise neurocognitive mechanism underlying it calls for further, ideally longitudinal, studies to establish its role as a potential contributor to, and/or consequence of, tinnitus.
-
- Neuroscience
Learning alters cortical representations and improves perception. Apical tuft dendrites in cortical layer 1, which are unique in their connectivity and biophysical properties, may be a key site of learning-induced plasticity. We used both two-photon and SCAPE microscopy to longitudinally track tuft-wide calcium spikes in apical dendrites of layer 5 pyramidal neurons in barrel cortex as mice learned a tactile behavior. Mice were trained to discriminate two orthogonal directions of whisker stimulation. Reinforcement learning, but not repeated stimulus exposure, enhanced tuft selectivity for both directions equally, even though only one was associated with reward. Selective tufts emerged from initially unresponsive or low-selectivity populations. Animal movement and choice did not account for changes in stimulus selectivity. Enhanced selectivity persisted even after rewards were removed and animals ceased performing the task. We conclude that learning produces long-lasting realignment of apical dendrite tuft responses to behaviorally relevant dimensions of a task.
