Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes
Open accessAbstract
Aim To investigate the effects of rapamycin on glutamate uptake in cultured rat astrocytes expressing N-terminal 552 residues of mutant huntingtin (Htt-552).Methods Primary astrocyte cultures were prepared from the cortex of postnatal rat pups. An astrocytes model of Huntington's disease was established using the astrocytes infected with adenovirus carrying coden gene of N-terminal 552 residues of Huntingtin. The protein levels of glutamate transporters GLT-1 and GLAST, the autophagic marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the autophagy substrate p62 in the astrocytes were examined using Western blotting. The mRNA expression levels of GLT-1 and GLAST in the astrocytes were determined using Real-time PCR. [(3)H]glutamate uptake by the astrocytes was measured with liquid scintillation counting.Results The expression of mutant Htt-552 in the astrocytes significantly decreased both the mRNA and protein levels of GLT-1 but not those of GLAST. Furthermore, Htt-552 significantly reduced [(3)H]glutamate uptake by the astrocytes. Treatment with the autophagy inhibitor 3-MA (10 mmol/L) significantly increased the accumulation of mutant Htt-552, and reduced the expression of GLT-1 and [(3)H]glutamate uptake in the astrocytes. Treatment with the autophagy stimulator rapamycin (0.2 mg/mL) significantly reduced the accumulation of mutant Htt-552, and reversed the changes in GLT-1 expression and [(3)H]glutamate uptake in the astrocytes.Conclusion Rapamcin, an autophagy stimulator, can prevent the suppression of GLT-1 expression and glutamate uptake by mutant Htt-552 in cultured astrocytes.
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Autophagy is responsible for degrading HTT in astrocytes and promotes glutamate transporter expression in these cells.
“not only is autophagy responsible for degrading HTT in astrocytes, but it also promotes glutamate transporter expression in these cells [413]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [413]
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- Authors
- Chen, L.-L., Wu, J.-C., Wang, L.-H., Wang, J., Qin, Z.-H., Difiglia, M., & Lin, F.
- Affiliations
- Soochow University (CN)
- Harvard University (US)
- Corresponding author
- Lin, Fang
- Venue
- Acta Pharmacologica Sinica
- Published
- 2012-01-23
- Volume
- 33
- Issue
- 3
- Pages
- 385-392
- ISSN
- 0253-9756 (ISSN-L)
- 1671-4083
- 1745-7254
- PMC
- PMC4077128
- OpenAlex
- W2007840958
- Cited by
- 26
- References
- 37
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 3
- FWCI
- 1.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Pharmacologica Sinica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (30600197)
- Soochow University
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- rapamycin, mutant huntingtin, GLT-1, glutamate transporters, astrocytes, Huntington's disease, autophagy, glutamate uptake, GLAST, LC3, p62, 3-methyladenine, adenoviral gene expression
- MeSH terms
- Huntingtin Protein, Animals, Astrocytes, Huntington Disease, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Rats, Sprague-Dawley, Sirolimus, Excitatory Amino Acid Transporter 2, Rats
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