S113R mutation in Slc33a1 leads to neurodegeneration and augmented BMP signaling in a mouse model
Open accessAbstract
The S113R mutation (c.339T>G) (MIM #603690.0001) in SLC33A1 (MIM #603690), an ER membrane acetyl-CoA transporter, has been previously identified in patients with hereditary spastic paraplegia type 42 (SPG42; MIM #612539). SLC33A1 has also been shown to inhibit bone morphogenetic protein (BMP) signaling pathway in zebrafish. To better understand the function of SLC33A1, we generated and characterized Slc33a1S113R knock-in mice. Homozygous Slc33a1S113R mutant mice were embryonic lethal, while heterozygous Slc33a1 mutant mice (Slc33a1wt/mut) exhibited behavioral abnormalities and central neurodegeneration, which is consistent with HSP phenotypes. Importantly, we found an upregulation of BMP signaling in the nervous system and mouse embryonic fibroblasts of Slc33a1wt/mut mice. Using a sciatic nerve crush injury model in vivo and dorsal root ganglion (DRG) culture in vitro we showed that injury-induced axonal regeneration in Slc33a1wt/mut mice was accelerated and was mediated by upregulated BMP signaling. Exogenous addition of BMP signaling antagonist, Noggin, could efficiently alleviate the accelerated injury-induced axonal regrowth. These results indicate that SLC33A1 can negatively regulate BMP signaling in mice, further supporting the notion that upregulation of BMP signaling is a common mechanism of a subset of hereditary spastic paraplegias.
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By using pooled CRISPR-Cas9 targeted screening, we discovered genes for which variants cause autosomal dominant forms of neurodegeneration (SLC33A1, SNX17, GRN, VPS35, CLN3, NPC2) as genetic modulators of lipid droplet formation in microglia.
“By using pooled CRISPR-Cas9 targeted screening, we discovered genes for which variants cause autosomal dominant forms of neurodegeneration (SLC33A1, SNX17, GRN, VPS35, CLN3, NPC2) as genetic modulators of lipid droplet formation in microglia32–35.”
From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [34]
GRN mutations are linked to the development of frontotemporal dementia, and GRN−/− mice are used as a model for FTD and are characterized by microglial changes, neuroinflammation, and cognitive deficits.
“GRN mutations are linked to the development of frontotemporal dementia (FTD)34, and GRN−/− mice are used as a model for FTD and are characterized by microglial changes, neuroinflammation, and cognitive deficits36.”
From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [34]
Citation 36 is attached to the claim about GRN−/− mice. The Results and Discussion passages concern Slc33a1-mutant mice and hereditary spastic paraplegia; searches for GRN, progranulin, FTD, microglial changes, neuroinflammation, and cognitive deficits found no passage addressing the GRN−/− model. The separate claim that GRN mutations are linked to FTD is attached to citation 34, not this source. (LLM, conf=0.76)
Experimental — accuracy not yet measuredGRN causes frontotemporal dementia in people with loss of function mutations.
“Excitingly, knockout of GRN, which causes frontotemporal dementia in people with loss of function mutations in this gene34, resulted in severe accumulation of lipid droplets in microglia in vivo.”
From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [34]
The Results and Discussion passages concern SLC33A1 mutations, hereditary spastic paraplegia, and BMP signaling, not GRN. Searches for GRN, progranulin, frontotemporal dementia, and loss-of-function mutations found no passage in our copy addressing the attributed claim. (LLM, conf=0.76)
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Research works printed but not linked: 18
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Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0566-1 · Cited by 1,384 · see citing works
- Authors
- Liu, P., Jiang, B., Ma, J., Lin, P., Zhang, Y., Shao, C., Sun, W., & Gong, Y.
- Affiliations
- Shandong University (CN)
- Corresponding author
- Sun, Wenjie
- Gong, Yaoqin
- Venue
- Disease Models & Mechanisms
- Publisher
- The Company of Biologists
- Published
- 2016-01-01
- Volume
- 10
- Issue
- 1
- Pages
- 53-62
- ISSN
- 1754-8403 (ISSN-L)
- 1754-8411
- PMC
- PMC5278525
- OpenAlex
- W2556639243
- Cited by
- 18
- References
- 0
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 1
- FWCI
- 0.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Disease Models & Mechanisms (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- International Science and Technology Cooperation Program of China (2013DFG32700)
- Key Research Program of Shandong Province (2015GSF118141)
- Natural Science Foundation of Shandong Province (ZR2015HZ002 ZR2016HQ19)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- BMP signaling, axon regeneration, sciatic nerve crush injury, dorsal root ganglia, noggin, knock-in mice, embryonic lethality
- MeSH terms
- Animals, Axons, Disease Models, Animal, Embryo, Mammalian, Ganglia, Spinal, Heterozygote, Homozygote, Motor Activity, Mutation, Nerve Degeneration, Nerve Regeneration, Phenotype, Sciatic Nerve, Signal Transduction, Up-Regulation, Survival Analysis, Bone Morphogenetic Proteins, Membrane Transport Proteins, Gene Knock-In Techniques
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