Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

Andrew Shum, Sofia Zaichick, Gregory S. McElroy, Karis D. Alessandro, Milad J. Alasady, Michaela Novakovic, Wesley Peng, Ekaterina A. Grebenik, Daayun Chung, Margaret E. Flanagan, Roger Smith, Alejandro Morales, Laetitia Stumpf, Kaitlyn McGrath, Dimitri Krainc, Marc L. Mendillo, Murali Prakriya, Navdeep S. Chandel, Gabriela Caraveo

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish (US)
Article numbere2217396120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Apr 25 2023
Externally publishedYes

ASJC Scopus subject areas

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