Causes and consequences of degeneration of the dorsal motor nucleus of the vagus nerve in Parkinson's disease.

SIGNIFICANCE: Parkinson's disease (PD) is no longer considered merely a movement disorder caused by degeneration of dopamine neurons in the midbrain. It is now recognized as a widespread neuropathological syndrome accompanied by a variety of motor and nonmotor clinical symptoms. As such, any hypothesis concerning PD pathogenesis and pathophysiology must account for the entire spectrum of disease and not solely focus on the dopamine system. RECENT ADVANCES: Based on its anatomy and the intrinsic properties of its neurons, the dorsal motor nucleus of the vagus nerve (DMV) is uniquely vulnerable to damage from PD. Fibers in the vagus nerve course throughout the gastrointestinal (GI) tract to and from the brainstem forming a close link between the peripheral and central nervous systems and a point of proximal contact between the environment and areas where PD pathology is believed to start. In addition, DMV neurons are under high levels of oxidative stress due to their high level of α-synuclein expression, fragile axons, and specific neuronal physiology. Moreover, several consequences of DMV damage, namely, GI dysfunction and unrestrained inflammation, may propagate a vicious cycle of injury affecting vulnerable brain regions. CRITICAL ISSUES: Current evidence to suggest the vagal system plays a pivotal role in PD pathogenesis is circumstantial, but given the current state of the field, the time is ripe to obtain direct experimental evidence to better delineate it. FUTURE DIRECTIONS: Better understanding of the DMV and vagus nerve may provide insight into PD pathogenesis and a neural highway with direct brain access that could be harnessed for novel therapeutic interventions.