title: Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease.
abstract: Parkinson's disease (PD) is a multifocal degenerative disorder for which there is no cure. The majority of cases are sporadic with unknown etiology. Recent data indicate that untreated patients with de novo PD have increased colonic permeability and that both de novo and premotor patients have pathological expression of α-synuclein (α-syn) in their colon. Both endpoints potentially can serve as disease biomarkers and even may initiate PD events through gut-derived, lipopolysaccharide (LPS)-induced neuronal injury. Animal models could be ideal for interrogating the potential role of the intestines in the pathogenesis of PD; however, few current animal models of PD encompass these nonmotor features. We sought to establish a progressive model of PD that includes the gastrointestinal (GI) dysfunction present in human patients. C57/BL6 mice were systemically administered one dose of either LPS (2.5 mg/kg) or saline and were sacrificed in monthly intervals (n = 5 mice for 5 months) to create a time-course. Small and large intestinal permeability was assessed by analyzing the urinary output of orally ingested sugar probes through capillary column gas chromatography. α-Syn expression was assessed by counting the number of mildly, moderately, and severely affected myenteric ganglia neurons throughout the GI tract, and the counts were validated by quantitative optical density measurements. Nigrostriatal integrity was assessed by tyrosine hydroxylase immunohistochemistry stereology and densitometry. LPS caused an immediate and progressive increase in α-syn expression in the large intestine but not in the small intestine. Intestinal permeability of the whole gut (large and small intestines) progressively increased between months 2 and 4 after LPS administration but returned to baseline levels at month 5. Selective measurements demonstrated that intestinal permeability in the small intestine remained largely intact, suggesting that gut leakiness was predominately in the large intestine. Phosphorylated serine 129-α-syn was identified in a subset of colonic myenteric neurons at months 4 and 5. Although these changes were observed in the absence of nigrostriatal degeneration, an abrupt but insignificant increase in brainstem α-syn was observed that paralleled the restoration of permeability. No changes were observed over time in controls. LPS, an endotoxin used to model PD, causes sequential increases in α-syn immunoreactivity, intestinal permeability, and pathological α-syn accumulation in the colon in a manner similar to that observed in patients with PD. These features are observed without nigrostriatal degeneration and incorporate PD features before the motor syndrome. This allows for the potential use of this model in testing neuroprotective and disease-modifying therapies, including intestinal-directed therapies to fortify intestinal barrier integrity.
authors.affiliation: Department of Neurosurgery, Rush University, Chicago, Illinois, USA; Department of Pharmacology, The Graduate College, Rush University, Chicago, Illinois, USA.
authors.forename: Leo P
authors.initials: LP
authors.lastname: Kelly
authors.forename: Paul M
authors.initials: PM
authors.lastname: Carvey
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Shannon
authors.forename: Maliha
authors.initials: M
authors.lastname: Shaikh
authors.forename: Roy A E
authors.initials: RA
authors.lastname: Bakay
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kordower
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002849:Chromatography, Gas; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005765:Gastrointestinal Agents / Q000652:urine; D016014:Linear Models; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000652:urine; D010539:Permeability / Q000187:drug effects; D011134:Polysaccharides / Q000633:toxicity; D012720:Severity of Illness Index; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014630:Vagus Nerve / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D005765:Gastrointestinal Agents; D011134:Polysaccharides; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase
keywords: Parkinson; animal model; enteric nervous system; synuclein