Elevated Levels of Arachidonic Acid-Derived Lipids Including Prostaglandins and Endocannabinoids Are Present Throughout ABHD12 Knockout Brains: Novel Insights Into the Neurodegenerative Phenotype

Derived from arachidonic acid (AA) , the endogenous cannabinoid (eCB) 2-arachidonoyl glycerol (2-AG) is a substrate for alpha/beta hydrolase domain-12 (ABHD12). Loss-of-function mutations of ABHD12 are associated with the neurodegenerative disorder polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC). ABHD12 knockout (KO) mice show PHARC-like behaviors in older adulthood. Here, we test the hypothesis that ABHD12 deletion age-dependently regulates bioactive lipids in the CNS. Lipidomics analysis of the brainstem, cerebellum, cortex, hippocampus, hypothalamus, midbrain, striatum and thalamus from male young (3-4 months) and older (7 months) adult ABHD12 KO and age-matched wild-type (WT) mice was performed on over 80 lipids via HPLC/MS/MS, including eCBs, lipoamines, 2-acyl glycerols, free fatty acids, and prostaglandins (PGs). Aging and ABHD12 deletion drove widespread changes in the CNS lipidome; however, the effects of ABHD12 deletion were similar between old and young mice, meaning that many alterations in the lipidome precede PHARC-like symptoms. AA-derived lipids were particularly sensitive to ABHD12 deletion. 2-AG increased in the striatum, hippocampus, cerebellum, thalamus, midbrain, and brainstem, whereas the eCB N-arachidonoyl ethanolamine (AEA) increased in all 8 brain regions, along with at least 2-PGs. Aging also had a widespread effect on the lipidome and more age-related changes in bioactive lipids were found in ABHD12 KO mice than WT suggesting that ABHD12 deletion exacerbates the effects of age. The most robust effects of aging (independent of genotype) across the CNS were decreases in N-acyl GABAs and N-acyl glycines. In conclusion, levels of bioactive lipids are dynamic throughout adulthood and deleting ABHD12 disrupts the wider lipidome, modulating multiple AA-derived lipids with potential consequences for neuropathology.