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Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

Octopamine is a well-established invertebrate neurotransmitter involved in fight or flight responses. In mammals, its function was replaced by epinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here,...

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Autores principales: Shum, Andrew, Zaichick, Sofia, McElroy, Gregory S., D’Alessandro, Karis, Alasady, Milad J., Novakovic, Michaela, Peng, Wesley, Grebenik, Ekaterina A., Chung, Daayun, Flanagan, Margaret E., Smith, Roger, Morales, Alejandro, Stumpf, Laetitia, McGrath, Kaitlyn, Krainc, Dimitri, Mendillo, Marc L., Prakriya, Murali, Chandel, Navdeep S., Caraveo, Gabriela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10151466/
https://www.ncbi.nlm.nih.gov/pubmed/37068235
http://dx.doi.org/10.1073/pnas.2217396120
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author Shum, Andrew
Zaichick, Sofia
McElroy, Gregory S.
D’Alessandro, Karis
Alasady, Milad J.
Novakovic, Michaela
Peng, Wesley
Grebenik, Ekaterina A.
Chung, Daayun
Flanagan, Margaret E.
Smith, Roger
Morales, Alejandro
Stumpf, Laetitia
McGrath, Kaitlyn
Krainc, Dimitri
Mendillo, Marc L.
Prakriya, Murali
Chandel, Navdeep S.
Caraveo, Gabriela
author_facet Shum, Andrew
Zaichick, Sofia
McElroy, Gregory S.
D’Alessandro, Karis
Alasady, Milad J.
Novakovic, Michaela
Peng, Wesley
Grebenik, Ekaterina A.
Chung, Daayun
Flanagan, Margaret E.
Smith, Roger
Morales, Alejandro
Stumpf, Laetitia
McGrath, Kaitlyn
Krainc, Dimitri
Mendillo, Marc L.
Prakriya, Murali
Chandel, Navdeep S.
Caraveo, Gabriela
author_sort Shum, Andrew
collection PubMed
description Octopamine is a well-established invertebrate neurotransmitter involved in fight or flight responses. In mammals, its function was replaced by epinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a trace amine-associated receptor 1–Orai1–Ca(2+)–calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the monocarboxylase transporter 2–calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halt lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a unique function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies.
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spelling pubmed-101514662023-05-03 Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein Shum, Andrew Zaichick, Sofia McElroy, Gregory S. D’Alessandro, Karis Alasady, Milad J. Novakovic, Michaela Peng, Wesley Grebenik, Ekaterina A. Chung, Daayun Flanagan, Margaret E. Smith, Roger Morales, Alejandro Stumpf, Laetitia McGrath, Kaitlyn Krainc, Dimitri Mendillo, Marc L. Prakriya, Murali Chandel, Navdeep S. Caraveo, Gabriela Proc Natl Acad Sci U S A Biological Sciences Octopamine is a well-established invertebrate neurotransmitter involved in fight or flight responses. In mammals, its function was replaced by epinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a trace amine-associated receptor 1–Orai1–Ca(2+)–calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the monocarboxylase transporter 2–calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halt lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a unique function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies. National Academy of Sciences 2023-04-17 2023-04-25 /pmc/articles/PMC10151466/ /pubmed/37068235 http://dx.doi.org/10.1073/pnas.2217396120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Shum, Andrew
Zaichick, Sofia
McElroy, Gregory S.
D’Alessandro, Karis
Alasady, Milad J.
Novakovic, Michaela
Peng, Wesley
Grebenik, Ekaterina A.
Chung, Daayun
Flanagan, Margaret E.
Smith, Roger
Morales, Alejandro
Stumpf, Laetitia
McGrath, Kaitlyn
Krainc, Dimitri
Mendillo, Marc L.
Prakriya, Murali
Chandel, Navdeep S.
Caraveo, Gabriela
Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein
title Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein
title_full Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein
title_fullStr Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein
title_full_unstemmed Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein
title_short Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein
title_sort octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10151466/
https://www.ncbi.nlm.nih.gov/pubmed/37068235
http://dx.doi.org/10.1073/pnas.2217396120
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