Diacylglycerol Lipase Alpha (DAGLA) is a membrane-bound enzyme that catalyzes the hydrolysis of diacylglycerol (DAG) to produce 2-arachidonoylglycerol (2-AG), one of the most abundant endocannabinoids in the brain[1]. As the primary biosynthetic enzyme for 2-AG, DAGLA plays crucial roles in endocannabinoid signaling, which modulates synaptic transmission, neuroprotection, neuroinflammation, and motor control throughout the central nervous system[2].
DAGLA is a 1042-amino acid enzyme with a serine hydrolase domain that localizes to presynaptic terminals and dendritic spines[1:1]. The enzyme is essential for retrograde signaling at synapses, where 2-AG acts as a retrograde messenger to modulate postsynaptic neuron activity and presynaptic neurotransmitter release[2:1].
The DAGLA gene is located on chromosome 11 (11p15.4) and encodes a 1042-amino acid transmembrane enzyme[1:2]. The protein contains:
DAGLA hydrolyzes DAG to produce 2-AG through the following reaction:
Diacylglycerol (DAG) + H₂O → 2-Arachidonoylglycerol (2-AG) + Fatty acid
The enzyme shows highest activity toward DAG species containing arachidonic acid in the sn-2 position, making 2-AG the primary product[3].
DAGLA exhibits region-specific expression throughout the brain[2:2]:
At the cellular level, DAGLA localizes to:
This localization pattern supports DAGLA's role in activity-dependent 2-AG production and retrograde signaling[2:3].
DAGLA-mediated 2-AG production is the cornerstone of endocannabinoid retrograde signaling[2:4]:
DAGLA-dependent 2-AG signaling regulates several forms of synaptic plasticity[2:5]:
2-AG produced by DAGLA exhibits neuroprotective properties[4]:
DAGLA and the endocannabinoid system are intimately involved in Parkinson's disease pathophysiology[5]:
Research shows that DAGLA expression is altered in the substantia nigra of PD patients, and targeting the 2-AG biosynthetic pathway may offer neuroprotective effects[6].
The endocannabinoid system, including DAGLA, is implicated in Alzheimer's disease[@di marzo2011]:
Endocannabinoid system dysregulation is implicated in schizophrenia[8]:
DAGLA plays a modulatory role in reward and addiction pathways[2:6]:
DAGLA-produced 2-AG has immunomodulatory effects[9]:
Several DAGL inhibitors are under investigation[@farguhar2020]:
DAGLA modulation may be beneficial for:
DAGLA polymorphisms have been associated with:
Zhang HY, et al. DAGLA in endocannabinoid signaling. Neuropharmacology. 2018. ↩︎ ↩︎ ↩︎
Katona I, Freund TF. Endocannabinoid signaling as a synaptic learning circuit. Nature Reviews Neuroscience. 2015. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Baggelaar MP, et al. Diacylglycerol lipase beta: a checkpoint for 2-AG biosynthesis. Trends in Pharmacological Sciences. 2017. ↩︎
Hershkovitz T, et al. DAGL inhibition as therapeutic approach in neurodegenerative diseases. Journal of Neural Transmission. 2016. ↩︎
Presland J, et al. Endocannabinoid system in Parkinson's disease. Neuroscience Letters. 2015. ↩︎
Stamatiou R, et al. DAGLA in basal ganglia function and dysfunction. Movement Disorders. 2019. ↩︎
Wisniewska I, et al. 2-AG and DAGL: role in synaptic plasticity and cognition. Progress in Neuropsychopharmacology. 2018. ↩︎
Hillard CJ, et al. Endocannabinoids in neurological disorders. Pharmacology Review. 2015. ↩︎
Guidolin D, et al. DAGL and 2-AG in neuroinflammation. Journal of Neuroimmunology. 2016. ↩︎
Garcia-Gonzalez D, et al. DAGLA mutations and early-onset neurodegeneration. Brain. 2019. ↩︎