Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

Shum, A.; Zaichick, S.; McElroy, G.; DAlessandro, K.; Novakovic, M.; Peng, W.; Chung, D.; Flanagan, M.; Smith, R.; Morales, A.; Stumpf, L.; McGrath, K.; Krainc, D.; Mendillo, M.; Prakriya, M.; Chandel, N.; Caraveo, G.

doi:10.1101/2022.10.04.510813

bioRxiv · 10.1101/2022.10.04.510813

Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

Shum, A.·Zaichick, S.·McElroy, G.·DAlessandro, K.·Novakovic, M.·Peng, W.·Chung, D.·Flanagan, M.·Smith, R.·Morales, A.·Stumpf, L.·McGrath, K.·Krainc, D.·Mendillo, M.·Prakriya, M.·Chandel, N.·Caraveo, G.

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Abstract

Octopamine is a well-established invertebrate neurotransmitter involved in fight-or-flight responses. In mammals, its function was replaced by norepinephrine. 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 -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 TAAR1-Orai1-Ca2+-calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the MCT2-calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by -synuclein halts lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a novel function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to -synucleinopathies.

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Shum, A., Zaichick, S., McElroy, G., DAlessandro, K., Novakovic, M., Peng, W., Chung, D., Flanagan, M., Smith, R., Morales, A., Stumpf, L., McGrath, K., Krainc, D., Mendillo, M., Prakriya, M., Chandel, N., Caraveo, G.. 2022-10-07. Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein. https://doi.org/10.1101/2022.10.04.510813

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