Interactions between cell adhesion and the synaptic vesicle cycle in Parkinson’s disease

Synaptic dysfunction has been identified as an early neuropathologic event in Parkinson’s disease. Synapses depend critically on the adhesion of neurons to one another, glial cells, and the extracellular matrix. Cell–cell and cell–matrix adhesions regulate the structure and function of synapses, in part, through interactions with structural elements such as actin and microtubule proteins. These proteins are critical not only for neuronal structure and polarity, but also for the synaptic vesicle cycle, including maintenance of and transfer between vesicle pools, exocytosis, and vesicle recycling. Pathway analyses of genome wide association studies (GWAS) in Parkinson’s disease have identified frequent single nucleotide polymorphisms (SNPs) in cell adhesion pathways, suggesting that dysfunction in cell adhesion may play a role in disease pathology. Based on these observations, it may be hypothesized that Parkinson’s disease is due to synaptic dysfunction caused by genetic variations in cell adhesion pathways that affect actin and/or microtubule-mediated events in the synaptic vesicle cycle. Furthermore, it is hypothesized that cells with pacemaker-like activity—a characteristic of neurons that degenerate in Parkinson’s disease—may depend more on actin for recruiting synaptic vesicles for release than do less active neurons, thereby enhancing their sensitivity to SNPs in cell adhesion pathways and explaining the selectivity of neurodegeneration. Cells may ultimately die due to detachment from the extracellular matrix. This hypothesis suggests that further exploration of cell adhesion pathways and their linkage to neurotransmitter release through cell structural proteins such as actin and microtubules may provide important insights into Parkinson’s disease.