Enteric glial cell and astrocyte melatonin regulation in Parkinson disease pathogenesis and pathophysiology

There is a growing frustration regarding the lack of progress in the prevention and treatment of Parkinson’s disease (PD). This article reviews wide bodies of data on PD pathophysiology and proposes that this lack of progress arises from a failure to investigate the role of the mitochondrial melatonergic pathway in enteric glial cells (PD pathogenesis) and astrocytes (PD ongoing pathophysiology). Recent work indicates that the melatonergic pathway is powerfully regulated by the interactions of canonical (nuclear translocating) and noncanonical (mitochondria translocating) STAT3 with NF-κB dimer composition. As both STAT3 and NF-κB have been extensively investigated in PD and shown to have significant etiological and pathophysiological importance, the incorporation of their interactions in the regulation of enteric glial cell and astrocyte melatonergic pathway provides a novel conceptualization of PD etiology and pathophysiology. Incorporating the mitochondrial melatonergic pathway in enteric glial cells and astrocytes has significant future research and treatment implications and better integrates wider bodies of data linked to PD, including the effects of type 2 diabetes; methylglyoxal; and why PD susceptibility is associated with a wide array of diverse medical conditions, including autism, bipolar disorder, schizophrenia, and depression. The suppression of the enteric glial cell melatonergic pathway is proposed to attenuate trophic support for enteroendocrine cells, thereby initiating α-synuclein upregulation in enteroendocrine cells and wider gut cells, which is transported via the vagal nerve to the CNS. Gut α-synuclein and/or mitochondrial antigens are proposed to prime CD8+ t cells for substantia nigra pars compacta (SNpc) dopamine neuron elimination. Suppression of the enteric glial cell melatonergic pathway also prevents vagal nerve stimulation from dampening gut inflammatory activity, which requires local gut melatonin production. Within the CNS, maintained astrocyte reactivity is associated with an attenuated capacity to upregulate the melatonergic pathway, which is proposed to arise from altered STAT3 phosphorylation interacting with NF-κB dimer composition. Reactive astrocytes expressing CD44 are proposed to guide gut-primed CD8+ t cells to eliminate SNpc dopamine neurons. The investigation of the astrocyte and enteric glial cell melatonergic pathway is an important future research direction that should better integrate wider bodies of previous disparate data pertaining to PD pathoetiology and pathophysiology and provide a conceptual framework for both prevention and symptom treatment.