Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila
- University College London, United Kingdom
- Max Planck Institute for Biology of Ageing, Germany
- University College of London, United Kingdom
Abstract
G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/Igf signalling is reduced in fly models of C9orf72 repeat expansion using RNA-sequencing of adult brain. We further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/Igf signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE151826. All data generated or analysed during this study are included in the manuscript.
Article and author information
Author details
Magda Luciana Atilano
Funding
Alzheimer's Research UK (ARUK-PG2016A-6)
- Adrian M Isaacs
Wellcome Trust
- Linda Partridge
Max-Planck-Gesellschaft (Open-access funding)
- Linda Partridge
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Atilano 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
-
- 2,749
- views
-
- 351
- downloads
-
- 23
- 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)
Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila
eLife 10:e58565.
https://doi.org/10.7554/eLife.58565
Further reading
-
- Neuroscience
Chronic pain is a prevalent and debilitating condition whose neural mechanisms are incompletely understood. An imbalance of cerebral excitation and inhibition (E/I), particularly in the medial prefrontal cortex (mPFC), is believed to represent a crucial mechanism in the development and maintenance of chronic pain. Thus, identifying a non-invasive, scalable marker of E/I could provide valuable insights into the neural mechanisms of chronic pain and aid in developing clinically useful biomarkers. Recently, the aperiodic component of the electroencephalography (EEG) power spectrum has been proposed to represent a non-invasive proxy for E/I. We, therefore, assessed the aperiodic component in the mPFC of resting-state EEG recordings in 149 people with chronic pain and 115 healthy participants. We found robust evidence against differences in the aperiodic component in the mPFC between people with chronic pain and healthy participants, and no correlation between the aperiodic component and pain intensity. These findings were consistent across different subtypes of chronic pain and were similarly found in a whole-brain analysis. Their robustness was supported by preregistration and multiverse analyses across many different methodological choices. Together, our results suggest that the EEG aperiodic component does not differentiate between people with chronic pain and healthy individuals. These findings and the rigorous methodological approach can guide future studies investigating non-invasive, scalable markers of cerebral dysfunction in people with chronic pain and beyond.
-
- Neuroscience
Recent studies suggest that calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) represent aversive information and signal a general alarm to the forebrain. If CGRP neurons serve as a true general alarm, their activation would modulate both passive nad active defensive behaviors depending on the magnitude and context of the threat. However, most prior research has focused on the role of CGRP neurons in passive freezing responses, with limited exploration of their involvement in active defensive behaviors. To address this, we examined the role of CGRP neurons in active defensive behavior using a predator-like robot programmed to chase mice. Our electrophysiological results revealed that CGRP neurons encode the intensity of aversive stimuli through variations in firing durations and amplitudes. Optogenetic activation of CGRP neuron during robot chasing elevated flight responses in both conditioning and retention tests, presumably by amyplifying the perception of the threat as more imminent and dangerous. In contrast, animals with inactivated CGRP neurons exhibited reduced flight responses, even when the robot was programmed to appear highly threatening during conditioning. These findings expand the understanding of CGRP neurons in the PBN as a critical alarm system, capable of dynamically regulating active defensive behaviors by amplifying threat perception, ensuring adaptive responses to varying levels of danger.
