Mechanistic impacts of bacterial diet on dopaminergic neurodegeneration in a Caenorhabditis elegans α-synuclein model of Parkinson’s disease
Anthony L. Gaeta,
Karolina Willicott,
Corey W. Willicott,
Luke E. McKay,
Candice M. Keogh,
Tyler J. Altman,
Logan C. Kimble,
Abigail L. Yarbrough,
Kim A. Caldwell,
Guy A. Caldwell
Affiliations
Anthony L. Gaeta
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Karolina Willicott
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Corey W. Willicott
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Luke E. McKay
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Candice M. Keogh
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Tyler J. Altman
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Logan C. Kimble
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Abigail L. Yarbrough
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Kim A. Caldwell
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA; Center for Convergent Bioscience and Medicine, The University of Alabama, Tuscaloosa, AL 35487, USA; Alabama Research Institute on Aging, The University of Alabama, Tuscaloosa, AL 35487, USA; Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center of Excellence for Basic Research in the Biology of Aging, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Guy A. Caldwell
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA; Center for Convergent Bioscience and Medicine, The University of Alabama, Tuscaloosa, AL 35487, USA; Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center of Excellence for Basic Research in the Biology of Aging, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Corresponding author
Summary: Failure of inherently protective cellular processes and misfolded protein-associated stress contribute to the progressive loss of dopamine (DA) neurons characteristic of Parkinson’s disease (PD). A disease-modifying role for the microbiome has recently emerged in PD, representing an impetus to employ the soil-dwelling nematode, Caenorhabditis elegans, as a preclinical model to correlate changes in gene expression with neurodegeneration in transgenic animals grown on distinct bacterial food sources. Even under tightly controlled conditions, hundreds of differentially expressed genes and a robust neuroprotective response were discerned between clonal C. elegans strains overexpressing human alpha-synuclein in the DA neurons fed either one of only two subspecies of Escherichia coli. Moreover, this neuroprotection persisted in a transgenerational manner. Genetic analysis revealed a requirement for the double-stranded RNA (dsRNA)-mediated gene silencing machinery in conferring neuroprotection. In delineating the contribution of individual genes, evidence emerged for endopeptidase activity and heme-associated pathway(s) as mechanistic components for modulating dopaminergic neuroprotection.
