A protective role for N-acylphosphatidylethanolamine phospholipase D in 6-OHDA-induced neurodegeneration

• Published in: Scientific reports Vol. 9; no. 1; pp. 15927 - 16
• Main Authors: Palese, Francesca, Pontis, Silvia, Realini, Natalia, Piomelli, Daniele
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-11-2019; Nature Publishing Group
• Subjects: 13; 13/109; 13/2; 13/51; 38; 38/39; 6-Hydroxydopamine; 631/378/1689/1718; 631/378/1934; 64; 64/110; 82; 82/29; 82/58; Animals; Apomorphine; Apomorphine - pharmacology; Apoptosis - drug effects; Caspase 3 - metabolism; Caspase-3; Cell death; Cell Line, Tumor; Cell Survival - drug effects; Clonal deletion; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine; Dopamine receptors; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Fibers; Homeostasis; Humanities and Social Sciences; Humans; Metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; Movement disorders; multidisciplinary; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neuroprotection; Neurotoxicity; Oxidopamine - pharmacology; Parkinson's disease; Phospholipase D; Phospholipase D - antagonists & inhibitors; Phospholipase D - genetics; Phospholipase D - metabolism; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Reactive oxygen species; Reactive Oxygen Species - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Substantia nigra; Transcription
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-51799-1

N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) catalyzes the cleavage of membrane NAPEs into bioactive fatty-acid ethanolamides (FAEs). Along with this precursor role, NAPEs might also serve autonomous signaling functions. Here, we report that injections of 6-hydroxydopamine (6-OHDA) into the mouse striatum cause a local increase in NAPE and FAE levels, which precedes neuronal cell death. NAPE, but not FAE, accumulation is enhanced in mice lacking NAPE-PLD, which display a substantial reduction in 6-OHDA-induced neurotoxicity, as shown by increased survival of substantia nigra dopamine neurons, integrity of striatal dopaminergic fibers, and striatal dopamine metabolite content. Reduced damage is accompanied by attenuation of the motor response evoked by apomorphine. Furthermore, NAPE-PLD silencing protects cathecolamine-producing SH-SY5Y cells from 6-OHDA-induced reactive oxygen species formation, caspase-3 activation and death. Mechanistic studies in mice suggest the existence of multiple molecular contributors to the neuroprotective effects of NAPE-PLD deletion, including suppression of Rac1 activity and attenuated transcription of several genes (
Cadps
,
Casp9
,
Egln1
,
Kcnj6
,
Spen
, and
Uchl1
) implicated in dopamine neuron survival and/or Parkinson’s disease. The findings point to a previously unrecognized role for NAPE-PLD in the regulation of dopamine neuron function, which may be linked to the control of NAPE homeostasis in membranes.