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

The diacylglycerol lipases, DAGLα and DAGLβ, hydrolyse diacylglycerol (DAG) to produce 2-arachidonoylglycerol (2-AG), a key endocannabinoid (eCB) and CB ₁ /CB ₂ receptor ligand. While DAGLα is well established as a regulator of CB ₁ -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 DAGLβ mRNA expression, demonstrating its co-expression with DAGLα mRNA predominantly in excitatory neurons throughout the adult nervous system. We see no evidence for enrichment of the DAGLs or CB ₁ 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, DAGLα-dependent 2-AG release at synapses relies on α-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 ₁ 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.