Senolytics: A Novel Strategy for Neuroprotection in ALS?
Abstract
:1. Amyotrophic Lateral Sclerosis: Prevalence, Causes, and Symptoms
2. Cellular Senescence in ALS
2.1. Senescence-Associated Beta-Galactosidase
2.2. Apoptosis-Related Pathways
2.3. Changes in Cell Cycle Inhibitor Levels
2.4. Senescence-Associated Secretory Phenotype
2.5. Loss of Glial Function
3. Senescence as a Therapeutic Target in ALS and Other CNS Diseases
4. Senolytic Agents and Their Limitations
Inducing Senolysis: The Challenge of Choosing a Signaling Pathway Target
5. Conclusions
Author Contributions
Funding
Informed Consent Statement
Conflicts of Interest
References
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Senolytic Agent | Mechanism of Action | Effects in Models of non-CNS Disorders | Effects in Models of CNS Disorders |
---|---|---|---|
17-DMAG | Hsp90 inhibition | Premature Aging Ercc1−/Δ model [62] ↓ p16-expressing embryonic mouse fibroblasts (V) ↓ p16 and SA-β-Gal (M) ↓ kyphosis; ↑ motor function and coordination (M) | ----- |
Quercetin (Q) | PI3K inhibition DNA intercalation | Premature Aging Ercc1−/Δ model (M) [18] ↓ p16 and SA-β-Gal ↑ bone density; ↑ ability to exercise | APP/PS1 model of AD (M) [52] ↓ SA-β-Gal; ↓ IL-6; ↓ microglial activation ↓ hippocampal Aβ plaque burden, TNF-α, and IL-1β, ↓ cognitive loss AD (M) [51] ↓ NFTs; ↓ atrophy in cortex ↑ blood flow in cerebellum Normal Aging (M) [55] ↑ maze performance; ↑ lamin B1 in neurons |
Dasatinib (D) | Akt inhibition | ||
Navitoclax | Non-selective Bcl-2 family inhibition | Senescence induced through radiation, oxidative stress, and excessive replication (V) [88] ↑ apoptosis of Bcl-xL- and Bcl-2-expressing HUVECs and IMR90 cells PN induced through cisplatin [54] ↓ p16 and p21 in DRG (V) ↓ mechanical and thermal thresholds of pain (M) | Tau-prone PS19 model of AD (M) [50] ↓ p16, p21, IL-6, and IL-1β expression ↓ phosphorylated tau |
A1331852 A1155463 | Selective Bcl-xL inhibition | Radiation-induced senescence (V) [89] ↑ apoptosis of Bcl-xL-expressing senescent HUVECs and IMR90 cells | ----- |
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Maximova, A.; Werry, E.L.; Kassiou, M. Senolytics: A Novel Strategy for Neuroprotection in ALS? Int. J. Mol. Sci. 2021, 22, 12078. https://doi.org/10.3390/ijms222112078
Maximova A, Werry EL, Kassiou M. Senolytics: A Novel Strategy for Neuroprotection in ALS? International Journal of Molecular Sciences. 2021; 22(21):12078. https://doi.org/10.3390/ijms222112078
Chicago/Turabian StyleMaximova, Alexandra, Eryn L. Werry, and Michael Kassiou. 2021. "Senolytics: A Novel Strategy for Neuroprotection in ALS?" International Journal of Molecular Sciences 22, no. 21: 12078. https://doi.org/10.3390/ijms222112078