Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of parkinsonism

The lysosomal cysteine hydrolase N-acylethanolamine acid amidase (NAAA) deactivates palmitoylethanolamide (PEA), a lipid-derived PPAR-alpha 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 phar-macological 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.

Automated summary

This study reveals the important role of NAAA-regulated PEA signaling in the survival of dopamine neurons and the development of Parkinson's disease symptoms. Deletion of the Naaa gene or inhibition of NAAA activity can significantly reduce neuron death and alleviate Parkinson's symptoms. Additionally, elevated NAAA expression is observed in the postmortem brain cortex and premortem blood-derived exosomes of Parkinson's disease patients. These findings suggest that NAAA could be a potential target for neuroprotective intervention.