Cargando…
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,...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1785035540246036480 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10151466 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT shumandrew octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT zaichicksofia octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT mcelroygregorys octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT dalessandrokaris octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT alasadymiladj octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT novakovicmichaela octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT pengwesley octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT grebenikekaterinaa octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT chungdaayun octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT flanaganmargarete octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT smithroger octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT moralesalejandro octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT stumpflaetitia octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT mcgrathkaitlyn octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT kraincdimitri octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT mendillomarcl octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT prakriyamurali octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT chandelnavdeeps octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein AT caraveogabriela octopaminemetabolicallyreprogramsastrocytestoconferneuroprotectionagainstasynuclein |