Naaa, also known as N-Acylethanolamine acid amidase, is an N-terminal cysteine hydrolase mainly located in the endosomal-lysosomal compartment of immune cells [1]. It catalyzes the hydrolytic deactivation of palmitoylethanolamide (PEA), a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist with anti-inflammatory effects. NAAA-regulated PEA signaling at PPAR-α is crucial for the induction and resolution of inflammation [1].

In mouse models, deletion of the Naaa gene or pharmacological inhibition of NAAA activity significantly attenuated dopamine neuron death and parkinsonian symptoms induced by mitochondrial neurotoxins [3]. Mice lacking NAAA in CD11b+ cells (monocytes, macrophages, and neutrophils) were resistant to the induction of hyperalgesic priming, while overexpression of NAAA or lack of PPAR-α in these cells led to constitutive priming [2]. In a traumatic brain injury (TBI) model, inactivation of NAAA increased PEA levels at the injured site, preventing early BBB damage and improving secondary injury [4]. In a psoriasis mouse model, genetic ablation of NAAA or local administration of its inhibitor F96 ameliorated psoriasis, while transgenic expression of NAAA accelerated its development [5].

In conclusion, Naaa plays a vital role in inflammation, pain, and neurodegeneration through regulating PEA-PPAR-α signaling. Findings from Naaa knockout or conditional knockout mouse models have revealed its significance in diseases such as Parkinson's disease, chronic pain, TBI, and psoriasis, suggesting it as a potential therapeutic target for these conditions.

References:

1. Piomelli, Daniele, Scalvini, Laura, Fotio, Yannick, Tarzia, Giorgio, Mor, Marco. 2020. N-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition. In Journal of medicinal chemistry, 63, 7475-7490. doi:10.1021/acs.jmedchem.0c00191. https://pubmed.ncbi.nlm.nih.gov/32191459/

2. Fotio, Yannick, Mabou Tagne, Alex, Squire, Erica, Mor, Marco, Piomelli, Daniele. 2024. NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice. In Nature communications, 15, 1705. doi:10.1038/s41467-024-46139-5. https://pubmed.ncbi.nlm.nih.gov/38402219/

3. Palese, Francesca, Pontis, Silvia, Realini, Natalia, Green, Kim, Piomelli, Daniele. 2022. Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of parkinsonism. In Pharmacological research, 182, 106338. doi:10.1016/j.phrs.2022.106338. https://pubmed.ncbi.nlm.nih.gov/35781057/

4. Li, Yitian, Zhou, Pan, Hu, Ting, Lu, Canzhong, Li, Yuhang. 2021. NAAA inhibitor F96 attenuates BBB disruption and secondary injury after traumatic brain injury (TBI). In European journal of pharmacology, 912, 174561. doi:10.1016/j.ejphar.2021.174561. https://pubmed.ncbi.nlm.nih.gov/34655598/

5. Li, Yuhang, Li, Yitian, Xu, Sennan, Qiu, Yan, Lu, Canzhong. 2022. N-Acylethanolamine acid amidase (NAAA) exacerbates psoriasis inflammation by enhancing dendritic cell (DCs) maturation. In Pharmacological research, 185, 106491. doi:10.1016/j.phrs.2022.106491. https://pubmed.ncbi.nlm.nih.gov/36244543/