TY - JOUR
T1 - Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein
AU - Shum, Andrew
AU - Zaichick, Sofia
AU - McElroy, Gregory S.
AU - Alessandro, Karis D.
AU - Alasady, Milad J.
AU - Novakovic, Michaela
AU - Peng, Wesley
AU - Grebenik, Ekaterina A.
AU - Chung, Daayun
AU - Flanagan, Margaret E.
AU - Smith, Roger
AU - Morales, Alejandro
AU - Stumpf, Laetitia
AU - McGrath, Kaitlyn
AU - Krainc, Dimitri
AU - Mendillo, Marc L.
AU - Prakriya, Murali
AU - Chandel, Navdeep S.
AU - Caraveo, Gabriela
N1 - Funding Information:
ACKNOWLEDGMENTS. Special thanks to M. Takahashi for critical reading of the manuscript. This work was supported by Northwestern University Clinical and Translational Sciences, Parkinson’s Foundation, and the National Institute of Neurological Disorders and Stroke Grant R01 NS117750.
Publisher Copyright:
© 2023 National Academy of Sciences. All rights reserved.
PY - 2023/4/25
Y1 - 2023/4/25
N2 - 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–Ca2+–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.
AB - 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–Ca2+–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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U2 - 10.1073/pnas.2217396120
DO - 10.1073/pnas.2217396120
M3 - Article
C2 - 37068235
AN - SCOPUS:85152658549
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 17
M1 - e2217396120
ER -