Sphingosine kinase 1-associated autophagy differs between neurons and astrocytes
Open accessAbstract
Autophagy is a degradative pathway for removing aggregated proteins, damaged organelles, and parasites. Evidence indicates that autophagic pathways differ between cell types. In neurons, autophagy plays a homeostatic role, compared to a survival mechanism employed by starving non-neuronal cells. We investigated if sphingosine kinase 1 (SK1)-associated autophagy differs between two symbiotic brain cell types—neurons and astrocytes. SK1 synthesizes sphingosine-1-phosphate, which regulates autophagy in non-neuronal cells and in neurons. We found that benzoxazine autophagy inducers upregulate SK1 and neuroprotective autophagy in neurons, but not in astrocytes. Starvation enhances SK1-associated autophagy in astrocytes, but not in neurons. In astrocytes, SK1 is cytoprotective and promotes the degradation of an autophagy substrate, mutant huntingtin, the protein that causes Huntington’s disease. Overexpressed SK1 is unexpectedly toxic to neurons, and its toxicity localizes to the neuronal soma, demonstrating an intricate relationship between the localization of SK1’s activity and neurotoxicity. Our results underscore the importance of cell type-specific autophagic differences in any efforts to target autophagy therapeutically.
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Autophagy is regulated by distinct mechanisms in different cell types, and these cell type-specific mechanisms underlie the differential vulnerability of separate tissues to autophagy mutations, resulting in heterogeneous manifestations of disease.
“Furthermore, mounting evidence shows that autophagy is regulated by distinct mechanisms in different cell types [11–26], and these cell type-specific mechanisms underlie the differential vulnerability of separate tissues to autophagy mutations, resulting in heterogenous manifestations of disease.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [11]
With global expression of germline mutations associated with ALS, neural and non-neural tissues manifest the detrimental effects of compromised autophagy, but to varying extents.
“with global expression of germline mutations associated with ALS, neural and non-neural tissues manifest the detrimental effects of compromised autophagy [11], but to varying extents [365,366]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [11]
Differences in autophagy between neurons and astrocytes may be due to enhanced phosphorylation of astrocytic SPHK1/SK1 with starvation, whereas benzoxazines activate neuronal but not astrocytic SPHK1 to induce autophagy.
“These differences in autophagy may be due to enhanced phosphorylation of astrocytic SPHK1/SK1 (sphingosine kinase 1) with starvation, whereas benzoxazines activate neuronal (but not astrocytic) SPHK1 to induce autophagy [11].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [11]
MTOR-independent activation of autophagy with benzoxazines takes place in neurons but not astrocytes.
“whereas MTOR-independent activation of autophagy with benzoxazines (e.g., 10-NCP and fluphenazine) takes place in neurons but not astrocytes [11].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [11]
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References 77 · Cited by 36
- Authors
- Moruno-Manchon, J. F., Uzor, N.-E., Ambati, C. R., Shetty, V., Putluri, N., Jagannath, C., McCullough, L. D., & Tsvetkov, A. S.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Tsvetkov, Andrey S.
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2018-05-09
- Volume
- 9
- Issue
- 5
- Pages
- 521-521
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC5943283
- OpenAlex
- W2801699830
- Cited by
- 36
- References
- 77
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 4 · 2022: 7 · 2021: 6 · 2020: 8 · 2019: 5 · 2018: 1
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Hereditary Disease Foundation
- Cancer Prevention and Research Institute of Texas (NCI-CA125123, P30CA125123, RP170005, CA125123)
- Dan L. Duncan Cancer Center, Baylor College of Medicine (P30 CA125123, CA125123)
- National Institutes of Health (RP170005, NCI-CA125123, CA125123)
- National Cancer Institute (R01CA220297, NCI-CA125123, CA125123, P30CA125123)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- sphingosine kinase 1, autophagy, neurons, astrocytes, sphingosine-1-phosphate, neuroprotection, starvation, mutant huntingtin, Huntington's disease, neurotoxicity
- MeSH terms
- Sphingosine Kinase, Animals, Astrocytes, Autophagy, Neurons, Organ Specificity, Phosphotransferases (Alcohol Group Acceptor), Rats
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