DAGLα/β, 2-AG release, and Parkinson's Disease: Exploring a causal link.

Abstract

The diacylglycerol lipases, DAGL and DAGL{beta}, hydrolyse diacylglycerol (DAG) to produce 2-arachidonoylglycerol (2-AG), a key endocannabinoid (eCB) and CB/CB2 receptor ligand. While DAGL is well established as a regulator of CB-dependent synaptic plasticity, recent studies have identified DAGLB mutations as a cause of autosomal recessive early-onset Parkinson's disease (PD). Here, we present a comprehensive analysis of DAGL{beta} mRNA expression, demonstrating its co-expression with DAGL mRNA predominantly in excitatory neurons throughout the adult nervous system. We see no evidence for enrichment of the DAGLs or CB transcripts in the striatum or in dopaminergic neurons. We discuss these findings within a review of recent literature that points to a wider involvement of the eCB system in PD. Notably, DAGL-dependent 2-AG release at synapses relies on -synuclein function - a protein central to PD pathophysiology-implicating both DAGLs in PD and pointing to widespread disruption in 2-AG release. Consistent with this, substantial reductions in 2-AG levels have been reported in the cerebrospinal fluid (CSF) of PD patients. Depression, a major non-motor symptom of PD, often precedes the onset of motor deficits by several years. Human and mouse genetic studies suggest that reduced DAGL activity may contribute to depression by impairing 2-AG-mediated CB receptor signalling, which is crucial for synaptic plasticity, stress resilience, and mood regulation. These findings point to a potential causal link between DAGL dysfunction and the non-motor symptoms in PD.