LRRK2 Expression in the Enteric Nervous System: ENSuring Its Significance

Excerpt

The hypothesis that the gut is a second brain arose in the early 1900s, when it was discovered that enteric nervous system (ENS) control of intestinal motility and secretion was largely independent of influences from the central nervous system (CNS). The ENS contains as many neurons as the spinal cord; the functional and chemical diversity of enteric neurons closely resembles that of the CNS. The ENS controls gut motility and secretion via local reflexes regulated by the liberation of specific neuromediators synthesized by functionally defined enteric neurons [1]. For example, among the most common neurotransmitters in the ENS, vasoactive intestinal peptide (VIP) and nitric oxide are often expressed in inhibitory muscle motoneurons, whereas acetylcholine and substance P are expressed in excitatory motoneurons. Aside from its well-recognized influences on gastrointestinal motility disorders, it has become evident over the last 20 years that the ENS is also substantially involved in Parkinson’s and Crohn’s diseases. At some point in the disease course, gastrointestinal symptoms occur in almost every Parkinson’s disease (PD) patient, clinical observations supported by postmortem studies that demonstrated the presence of alpha-synuclein inclusions, the defining neuropathological hallmark of the disease, in the ENS of almost all Parkinsonian subjects [2]. In Crohn’s disease, a number of studies consistently reported quantitative and qualitative changes in the neurochemical composition of enteric neurons in the small intestine and in the rectum [3, 4]. Remarkably, genome-wide association studies identified leucine-rich repeat kinase 2 (LRRK2), the most common gene implicated in the pathogenesis of autosomal dominant PD, as one of the susceptibility genes for Crohn’s disease [5]. These genetic data have been supported by a recent Taiwanese epidemiological study, which reported an increased risk of PD among individuals with Crohn’s disease [6]. …