Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

Abstract

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.

Harnessing IGF-1 and IL-2 as biomarkers for calcineurin activity to tailor optimal FK506 dosage in α-synucleinopathies

“…In an unbiased transcriptional approach using RNA sequencing (RNA-Seq), we previously found that one of the most prominent upregulated genes in α-syn neuronal cultures treated with neuroprotective doses of FK506 was the IGF-1 signaling pathway ( Shum et al, 2023 ). IGF-1 signaling has been shown to be neuroprotective, partially due to its role in inhibiting neuroinflammation ( Sukhanov et al, 2007 ; Park et al, 2011 ).…”

“…Based on the previous work through candidate and unbiased approaches ( Caraveo et al, 2014 ; Shum et al, 2023 ), we have now identified two plausible biomarkers responsive to the neuroprotective properties of FK506 in vivo : IL-2 and IGF-1. IL-2 expression is primarily regulated by NFAT, a bona fide calcineurin substrate ( Serfling et al, 2000 ; Bueno et al, 2002 ; Hogan et al, 2003 ; Macian, 2005 ).…”

“…IGF-1 expression can be regulated by calcineurin via NFAT ( Alfieri et al, 2007 ) or by NF-κB via IkB kinase, a substrate for calcineurin ( Mitsiades et al, 2002 ). Although IGF-1 can be produced by various cell types in the body, in CNS, neurons and glial cells, mainly astrocytes, serve as the main sources ( Labandeira-Garcia et al, 2017 ; Shum et al, 2023 ). Importantly, treatment with IGF-1 has been shown to ameliorate α-syn proteotoxicity ( Kao, 2009 ) and dopamine-induced neurotoxicity ( Offen et al, 2001 ).…”

“…Overexpressing SNARE proteins involved in endoplasmic reticulum (ER) to Golgi transport overcome the vesicular arrest between the ER and Golgi caused by α-syn ( Cooper et al, 2006 ; Gitler et al, 2008 ). Moreover, using this model, we and others found that α-syn leads to a pathological increase in cytosolic Ca 2+ , resulting in cell death ( Chan et al, 2007 ; Danzer et al, 2007 ; Dufty et al, 2007 ; Guzman et al, 2010 ; Surmeier et al, 2010 ; Goldberg et al, 2012 ; Martin et al, 2012 ; Buttner et al, 2013 ; Hurley et al, 2013 ; Yuan et al, 2013 ; Caraveo et al, 2014 ; Surmeier et al, 2016 ; Caraveo et al, 2017 ; Surmeier et al, 2017 ; Betzer et al, 2018 ; Shum et al, 2023 ). Some data suggest that the source of this pathological elevation could be either Ca 2+ uptake at the plasma membrane via the L-type voltage-gated Ca 2+ channel Cav1.3 ( Brown et al, 2006 ; Chan et al, 2007 ; Ilijic et al, 2011 ; Hurley and Dexter, 2012 ; Van Maele-Fabry et al, 2012 ; Dryanovski et al, 2013 ; Cali et al, 2014 ; Goldman, 2014 ; Schapira, 2015 ; Ortner and Striessnig, 2016 ; Surmeier et al, 2016 ; Zamponi, 2016 ) or α-syn itself, as its oligomeric conformation has the ability to form pores at the plasma membrane ( Danzer et al, 2007 ; Angelova et al, 2016 ; Di Scala et al, 2016 ).…”