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Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes
Macroautophagy dysregulation is implicated in multiple neurological disorders, such as Parkinson's disease. While autophagy pathways are heavily researched in heterologous cells and neurons, regulation of autophagy in the astrocyte, the most abundant cell type in the mammalian brain, is less we...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258991/ https://www.ncbi.nlm.nih.gov/pubmed/34126070 http://dx.doi.org/10.1016/j.jbc.2021.100873 |
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author | Pan, Ping-Yue Zhu, Justin Rizvi, Asma Zhu, Xinyu Tanaka, Hikari Dreyfus, Cheryl F. |
author_facet | Pan, Ping-Yue Zhu, Justin Rizvi, Asma Zhu, Xinyu Tanaka, Hikari Dreyfus, Cheryl F. |
author_sort | Pan, Ping-Yue |
collection | PubMed |
description | Macroautophagy dysregulation is implicated in multiple neurological disorders, such as Parkinson's disease. While autophagy pathways are heavily researched in heterologous cells and neurons, regulation of autophagy in the astrocyte, the most abundant cell type in the mammalian brain, is less well understood. Missense mutations in the Synj1 gene encoding Synaptojanin1 (Synj1), a neuron-enriched lipid phosphatase, have been linked to Parkinsonism with seizures. Our previous study showed that the Synj1 haploinsufficient (Synj1(+/−)) mouse exhibits age-dependent autophagy impairment in multiple brain regions. Here, we used cultured astrocytes from Synj1-deficient mice to investigate its role in astrocyte autophagy. We report that Synj1 is expressed in low levels in astrocytes and represses basal autophagosome formation. We demonstrate using cellular imaging that Synj1-deficient astrocytes exhibit hyperactive autophagosome formation, represented by an increase in the size and number of GFP-microtubule-associated protein 1A/1B-light chain 3 structures. Interestingly, Synj1 deficiency is also associated with an impairment in stress-induced autophagy clearance. We show, for the first time, that the Parkinsonism-associated R839C mutation impacts autophagy in astrocytes. The impact of this mutation on the phosphatase function of Synj1 resulted in elevated basal autophagosome formation that mimics Synj1 deletion. We found that the membrane expression of the astrocyte-specific glucose transporter GluT-1 was reduced in Synj1-deficient astrocytes. Consistently, AMP-activated protein kinase activity was elevated, suggesting altered glucose sensing in Synj1-deficient astrocytes. Expressing exogenous GluT-1 in Synj1-deficient astrocytes reversed the autophagy impairment, supporting a role for Synj1 in regulating astrocyte autophagy via disrupting glucose-sensing pathways. Thus, our work suggests a novel mechanism for Synj1-related Parkinsonism involving astrocyte dysfunction. |
format | Online Article Text |
id | pubmed-8258991 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-82589912021-07-12 Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes Pan, Ping-Yue Zhu, Justin Rizvi, Asma Zhu, Xinyu Tanaka, Hikari Dreyfus, Cheryl F. J Biol Chem Research Article Macroautophagy dysregulation is implicated in multiple neurological disorders, such as Parkinson's disease. While autophagy pathways are heavily researched in heterologous cells and neurons, regulation of autophagy in the astrocyte, the most abundant cell type in the mammalian brain, is less well understood. Missense mutations in the Synj1 gene encoding Synaptojanin1 (Synj1), a neuron-enriched lipid phosphatase, have been linked to Parkinsonism with seizures. Our previous study showed that the Synj1 haploinsufficient (Synj1(+/−)) mouse exhibits age-dependent autophagy impairment in multiple brain regions. Here, we used cultured astrocytes from Synj1-deficient mice to investigate its role in astrocyte autophagy. We report that Synj1 is expressed in low levels in astrocytes and represses basal autophagosome formation. We demonstrate using cellular imaging that Synj1-deficient astrocytes exhibit hyperactive autophagosome formation, represented by an increase in the size and number of GFP-microtubule-associated protein 1A/1B-light chain 3 structures. Interestingly, Synj1 deficiency is also associated with an impairment in stress-induced autophagy clearance. We show, for the first time, that the Parkinsonism-associated R839C mutation impacts autophagy in astrocytes. The impact of this mutation on the phosphatase function of Synj1 resulted in elevated basal autophagosome formation that mimics Synj1 deletion. We found that the membrane expression of the astrocyte-specific glucose transporter GluT-1 was reduced in Synj1-deficient astrocytes. Consistently, AMP-activated protein kinase activity was elevated, suggesting altered glucose sensing in Synj1-deficient astrocytes. Expressing exogenous GluT-1 in Synj1-deficient astrocytes reversed the autophagy impairment, supporting a role for Synj1 in regulating astrocyte autophagy via disrupting glucose-sensing pathways. Thus, our work suggests a novel mechanism for Synj1-related Parkinsonism involving astrocyte dysfunction. American Society for Biochemistry and Molecular Biology 2021-06-11 /pmc/articles/PMC8258991/ /pubmed/34126070 http://dx.doi.org/10.1016/j.jbc.2021.100873 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Pan, Ping-Yue Zhu, Justin Rizvi, Asma Zhu, Xinyu Tanaka, Hikari Dreyfus, Cheryl F. Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes |
title | Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes |
title_full | Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes |
title_fullStr | Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes |
title_full_unstemmed | Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes |
title_short | Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes |
title_sort | synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258991/ https://www.ncbi.nlm.nih.gov/pubmed/34126070 http://dx.doi.org/10.1016/j.jbc.2021.100873 |
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