MitoPark transgenic mouse model recapitulates the gastrointestinal dysfunction and gut-microbiome changes of Parkinson’s disease

Thumbnail Image
Date
2019-12
Authors
Ghaisas, Shivani
Langley, Monica R.
Palanisamy, Bharathi N.
Dutta, Somak
Narayanaswamy, Kirthi
Sarkar, Souvarish
Ay, Muhammet
Jin, Huajun
Anantharam, Vellareddy
Major Professor
Advisor
Committee Member
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier B.V.
Authors
Person
Plummer, Paul
Associate Dean for Research and Graduate Studies
Research Projects
Organizational Units
Organizational Unit
Veterinary Diagnostic and Production Animal Medicine
The mission of VDPAM is to educate current and future food animal veterinarians, population medicine scientists and stakeholders by increasing our understanding of issues that impact the health, productivity and well-being of food and fiber producing animals; developing innovative solutions for animal health and food safety; and providing the highest quality, most comprehensive clinical practice and diagnostic services. Our department is made up of highly trained specialists who span a wide range of veterinary disciplines and species interests. We have faculty of all ranks with expertise in diagnostics, medicine, surgery, pathology, microbiology, epidemiology, public health, and production medicine. Most have earned certification from specialty boards. Dozens of additional scientists and laboratory technicians support the research and service components of our department.
Organizational Unit
Statistics

The Department of Statistics seeks to teach students in the theory and methodology of statistics and statistical analysis, preparing its students for entry-level work in business, industry, commerce, government, or academia.

History
The Department of Statistics was formed in 1948, emerging from the functions performed at the Statistics Laboratory. Originally included in the College of Sciences and Humanities, in 1971 it became co-directed with the College of Agriculture.

Dates of Existence
1948-present

Related Units

Organizational Unit
Veterinary Microbiology and Preventive Medicine
Our faculty promote the understanding of causes of infectious disease in animals and the mechanisms by which diseases develop at the organismal, cellular and molecular levels. Veterinary microbiology also includes research on the interaction of pathogenic and symbiotic microbes with their hosts and the host response to infection.
Organizational Unit
Office of Biotechnology
The Office of Biotechnology facilitates and advances programs in research, education, and outreach that contribute to the goals of Iowa State University’s Strategic Plan in the area of biotechnology. The Office oversees the biotechnology programs developed by the university’s Biotechnology Council and the Office of the Vice President for Research. The Office of Biotechnology works with the university’s biotechnology faculty and administrators to ensure effectiveness in research, education, and technology transfer related to the application of molecular biology to the development of useful products and processes.
Journal Issue
Is Version Of
Versions
Series
Abstract
Gastrointestinal (GI) disturbances are one of the earliest symptoms affecting most patients with Parkinson’s disease (PD). In many cases, these symptoms are observed years before motor impairments become apparent. Hence, the molecular and cellular underpinnings that contribute to this early GI dysfunction in PD have actively been explored using a relevant animal model. The MitoPark model is a chronic, progressive mouse model recapitulating several key pathophysiological aspects of PD. However, GI dysfunction and gut microbiome changes have not been categorized in this model. Herein, we show that decreased GI motility was one of the first non-motor symptoms to develop, evident as early as 8 weeks with significantly different transit times from 12 weeks onwards. These symptoms were observed well before motor symptoms developed, thereby paralleling PD progression in humans. At age 24 weeks, we observed increased colon transit time and reduced fecal water content, indicative of constipation. Intestinal inflammation was evidenced with increased expression of iNOS and TNFα in the small and large intestine. Specifically, iNOS was observed mainly in the enteric plexi, indicating enteric glial cell activation. A pronounced loss of tyrosine hydroxylase-positive neurons occurred at 24 weeks both in the mid-brain region as well as the gut, leading to a corresponding decrease in dopamine (DA) production. We also observed decreased DARPP-32 expression in the colon, validating the loss of DAergic neurons in the gut. However, the total number of enteric neurons did not significantly differ between the two groups. Metabolomic gas chromatography-mass spectrometry analysis of fecal samples showed increased sterol, glycerol, and tocopherol production in MitoPark mice compared to age-matched littermate controls at 20 weeks of age while 16 s microbiome sequencing showed a transient temporal increase in the genus Prevotella. Altogether, the data shed more light on the role of the gut dopaminergic system in maintaining intestinal health. Importantly, this model recapitulates the chronology and development of GI dysfunction along with other non-motor symptoms and can become an attractive translational animal model for pre-clinical assessment of the efficacy of new anti-Parkinsonian drugs that can alleviate GI dysfunction in PD.
Comments
This is a manuscript of an article published as Ghaisas, Shivani, Monica R. Langley, Bharathi N. Palanisamy, Somak Dutta, Kirthi Narayanaswamy, Paul J. Plummer, Souvarish Sarkar et al. "MitoPark transgenic mouse model recapitulates the gastrointestinal dysfunction and gut-microbiome changes of Parkinson’s disease." Neurotoxicology 75 (2019): 186-199. DOI: 10.1016/j.neuro.2019.09.004. Copyright 2019 Elsevier B.V. Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0). Posted with permission.
Description
Keywords
Citation
DOI
Copyright
Collections