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| Status |
Public on Apr 01, 2023 |
| Title |
Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 a-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. Neuron-derived octopamine acts on astrocytes via a TAAR1-Orai1-Ca2+-calcineurinmediated 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 a-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 hence neuroprotection with implications to a-synucleinopathies.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for rat primary neuronal cultures infected with either control or alpha synuclein-A53T variant and treated with either sub-saturating (0.2 µM) or saturating (2.0 µM) doses of FK506 or the vehicle control DMSO.
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| Contributor(s) |
Shum A, Zaichick S, McElroy GS, D’Alessandro K, Novakovic M, Peng W, Chung D, Flanagan ME, Smith R, Morales A, Stumpf L, McGrath K, Krainc D, Mendillo ML, Prakriya M, Chandel NS, Caraveo G |
| Citation(s) |
37068235 |
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| Submission date |
Sep 21, 2022 |
| Last update date |
Jul 01, 2023 |
| Contact name |
Marc L Mendillo |
| E-mail(s) |
mendillo@northwestern.edu
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| Organization name |
Northwestern University
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| Street address |
303 E Superior St
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| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60611 |
| Country |
USA |
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| Platforms (1) |
| GPL20084 |
Illumina NextSeq 500 (Rattus norvegicus) |
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| Samples (17)
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| Relations |
| BioProject |
PRJNA882845 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE213875_htseq.normCounts_GEO.txt.gz |
1.1 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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