Peptidoglycan recognition protein genes and risk of Parkinson's disease.

Parkinson’s disease (PD) is now thought of as a systemic disorder. Non-motor symptoms such as hyposmia and constipation sometimes precede motor symptoms by years to decades,1–4 and associated α-synuclein pathology in the autonomic and enteric nervous systems may precede development of pathological conditions in the brain.5–8 Some have proposed that PD begins in the gut and moves to the brain by one of several possible mechanisms. These include retrograde axonal transport of a toxic or infectious agent,9–11 neuron-to-neuron transmission of α-synuclein protein aggregates,6,12,13 or a prion-like seeding process.14,15 The gut has the largest mucosal surface of the body and is thus a primary anatomic target for exposure to toxicants and infectious agents. Recent reports suggest that patients with early PD may manifest increased intestinal permeability, bacterial invasion, and high levels of inflammatory cytokines in colonic biopsy specimens.16,17 The gut microbiota, comprising the trillions of organisms that line the length of the gastrointestinal tract, may play a role in PD. Systemic administration of gram-negative bacterial endotoxin (lipopolysaccharide [LPS]) activates microglia in the substantia nigra and induces progressive dopaminergic degeneration in a rodent model of parkinsonism.18 However, little is known about possible effects of other bacterial components. Peptidoglycan is a major structural component of the bacterial cell wall that serves to protect the plasma membrane. Because it is unique to bacteria, it is recognized as foreign and binds pattern recognition receptors, potently triggering an innate immune response.19 Humans have four peptidoglycan recognition proteins (PGRPs), highly conserved innate immunity proteins encoded by PGLYRPs 1–4, which are selectively expressed in a range of tissues and are also secreted into the gut.20 The PGRPs modulate the immune response to advantageous and harmful gut bacteria and play a major role in the development and maintenance of a healthy commensal microbiota,20 and variants in PGLYRP genes have recently been associated with risk of inflammatory bowel disease.21 We hypothesized that variation in PGLYRP genes might affect the risk of PD and tested this hypothesis in two independent study populations.