1. Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of parkinsonism.
- Author
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Palese, Francesca, Pontis, Silvia, Realini, Natalia, Torrens, Alexa, Ahmed, Faizy, Assogna, Francesca, Pellicano, Clelia, Bossù, Paola, Spalletta, Gianfranco, Green, Kim, and Piomelli, Daniele
- Subjects
Animals ,Humans ,Mice ,Neuroblastoma ,Parkinsonian Disorders ,Disease Models ,Animal ,Nerve Degeneration ,Dopamine ,Oxidopamine ,1-Methyl-4-phenyl-1 ,2 ,3 ,6-tetrahydropyridine ,Amidohydrolases ,Enzyme Inhibitors ,Dopaminergic Neurons ,N-Acylethanolamine Acid Amidase ,Neurodegeneration ,Neuroinflammation ,Palmitoylethanolamide ,Parkinson's disease ,Brain Disorders ,Biotechnology ,Parkinson's Disease ,Neurodegenerative ,Neurosciences ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Parkinson?s disease ,Pharmacology and Pharmaceutical Sciences ,Pharmacology & Pharmacy - Abstract
The lysosomal cysteine hydrolase N-acylethanolamine acid amidase (NAAA) deactivates palmitoylethanolamide (PEA), a lipid-derived PPAR-α agonist that is critically involved in the control of pain and inflammation. In this study, we asked whether NAAA-regulated PEA signaling might contribute to dopamine neuron degeneration and parkinsonism induced by the mitochondrial neurotoxins, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In vitro experiments showed that 6-OHDA and MPTP enhanced NAAA expression and lowered PEA content in human SH-SY5Y cells. A similar effect was observed in mouse midbrain dopamine neurons following intra-striatal 6-OHDA injection. Importantly, deletion of the Naaa gene or pharmacological inhibition of NAAA activity substantially attenuated both dopamine neuron death and parkinsonian symptoms in mice treated with 6-OHDA or MPTP. Moreover, NAAA expression was elevated in postmortem brain cortex and premortem blood-derived exosomes from persons with Parkinson's disease compared to age-matched controls. The results identify NAAA-regulated PEA signaling as a molecular control point for dopaminergic neuron survival and a potential target for neuroprotective intervention.
- Published
- 2022