Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival
Open accessAbstract
Delaying clinical disease onset would greatly reduce neurodegenerative disease burden, but the mechanisms influencing early preclinical progression are poorly understood. Here, we show that in mouse models of familial motoneuron (MN) disease, SOD1 mutants specifically render vulnerable MNs dependent on endogenous neuroprotection signaling involving excitability and mammalian target of rapamycin (mTOR). The most vulnerable low-excitability FF MNs already exhibited evidence of pathology and endogenous neuroprotection recruitment early postnatally. Enhancing MN excitability promoted MN neuroprotection and reversed misfolded SOD1 (misfSOD1) accumulation and MN pathology, whereas reducing MN excitability augmented misfSOD1 accumulation and accelerated disease. Inhibiting metabotropic cholinergic signaling onto MNs reduced ER stress, but enhanced misfSOD1 accumulation and prevented mTOR activation in alpha-MNs. Modulating excitability and/or alpha-MN mTOR activity had comparable effects on the progression rates of motor dysfunction, denervation, and death. Therefore, excitability and mTOR are key endogenous neuroprotection mechanisms in motoneurons to counteract clinically important disease progression in ALS.
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SOD1 mutants render vulnerable motor neurons dependent on endogenous neuroprotection signaling involving mTOR.
“SOD1 mutants specifically render vulnerable motor neurons dependent on endogenous neuroprotection signaling involving excitability and mechanistic target of rapamycin (mTOR; Leibinger et al., 2012; Saxena et al., 2013).”
From Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells (2017) · cites this paper as Saxena et al., 2013
mTOR activity in motor neurons influences the progression rates of motor dysfunction, muscle denervation and cell death in fALS.
“Moreover, mTOR activity in motor neurons influenced the progression rates of motor dysfunction, muscle denervation and cell death, suggesting that mTOR signaling is required for endogenous neuroprotection to counteract disease progression in fALS (Saxena et al., 2013).”
From Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells (2017) · cites this paper as Saxena et al., 2013
mTOR signaling is required for endogenous neuroprotection to counteract disease progression in fALS.
“Moreover, mTOR activity in motor neurons influenced the progression rates of motor dysfunction, muscle denervation and cell death, suggesting that mTOR signaling is required for endogenous neuroprotection to counteract disease progression in fALS (Saxena et al., 2013).”
From Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells (2017) · cites this paper as Saxena et al., 2013
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Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders
Hardingham, G. E., & Bading, H. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2911 · Cited by 1,644 · cited 2× · see citing works
“Furthermore, excitability and synaptic calcium entry have been related to neuroprotective signaling (Hardingham and Bading, 2010).”
Greer, P. L., & Greenberg, M. E. (2008) · Neuron · doi:10.1016/j.neuron.2008.09.002 · Cited by 661 · see citing works
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Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration
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“…neurons dependent on endogenous neuroprotection signaling involving excitability and mechanistic target of rapamycin (mTOR; Leibinger et al., 2012; Saxena et al., 2013). mTOR signaling senses extracellular stimuli and regulates many biological processes, such as cell growth, energy metabolism and…”
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- Authors
- Saxena, S., Roselli, F., Singh, K., Leptien, K., Julien, J.-P., Gros-Louis, F., & Caroni, P.
- Affiliations
- University of Bern (CH)
- Friedrich Miescher Institute (CH)
- Université Laval (CA)
- Corresponding author
- Caroni, Pico
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 80
- Issue
- 1
- Pages
- 80-96
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2058183189
- Cited by
- 275
- References
- 5
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 14 · 2023: 15 · 2022: 16 · 2021: 24 · 2020: 28 · 2019: 23 · 2018: 23 · 2017: 25 · 2016: 24 · 2015: 29 · 2014: 20 · 2013: 2
- FWCI
- 15.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- amyotrophic lateral sclerosis, motor neurons, neuroprotection, neuronal excitability, mTOR signaling, SOD1 misfolding, familial ALS, endoplasmic reticulum stress, alpha motoneurons, disease progression, motor neuron disease
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Brain, Cell Survival, Disease Models, Animal, Male, Mice, Transgenic, Motor Neurons, Mutation, Superoxide Dismutase, Signal Transduction, Mice, TOR Serine-Threonine Kinases
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