title: Investigating bacterial sources of toxicity as an environmental contributor to dopaminergic neurodegeneration.
abstract: Parkinson disease (PD) involves progressive neurodegeneration, including loss of dopamine (DA) neurons from the substantia nigra. Select genes associated with rare familial forms of PD function in cellular pathways, such as the ubiquitin-proteasome system (UPS), involved in protein degradation. The misfolding and accumulation of proteins, such as alpha-synuclein, into inclusions termed Lewy Bodies represents a clinical hallmark of PD. Given the predominance of sporadic PD among patient populations, environmental toxins may induce the disease, although their nature is largely unknown. Thus, an unmet challenge surrounds the discovery of causal or contributory neurotoxic factors that could account for the prevalence of sporadic PD. Bacteria within the order Actinomycetales are renowned for their robust production of secondary metabolites and might represent unidentified sources of environmental exposures. Among these, the aerobic genera, Streptomyces, produce natural proteasome inhibitors that block protein degradation and may potentially damage DA neurons. Here we demonstrate that a metabolite produced by a common soil bacterium, S. venezuelae, caused DA neurodegeneration in the nematode, Caenorhabditis elegans, which increased as animals aged. This metabolite, which disrupts UPS function, caused gradual degeneration of all neuronal classes examined, however DA neurons were particularly vulnerable to exposure. The presence of DA exacerbated toxicity because neurodegeneration was attenuated in mutant nematodes depleted for tyrosine hydroxylase (TH), the rate-limiting enzyme in DA production. Strikingly, this factor caused dose-dependent death of human SH-SY5Y neuroblastoma cells, a dopaminergic line. Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule. Evidence of a robust neurotoxic factor that selectively impacts neuronal survival in a progressive yet moderate manner is consistent with the etiology of age-associated neurodegenerative diseases. Collectively, these data suggest the potential for exposures to the metabolites of specific common soil bacteria to possibly represent a contributory environmental component to PD.
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, United States of America. kcaldwel@bama.ua.edu
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Tucci
authors.forename: Jafa
authors.initials: J
authors.lastname: Armagost
authors.forename: Tyler W
authors.initials: TW
authors.lastname: Hodges
authors.forename: Jue
authors.initials: J
authors.lastname: Chen
authors.forename: Shermeen B
authors.initials: SB
authors.lastname: Memon
authors.forename: Jeana E
authors.initials: JE
authors.lastname: Blalock
authors.forename: Susan M
authors.initials: SM
authors.lastname: DeLeon
authors.forename: Robert H
authors.initials: RH
authors.lastname: Findlay
authors.forename: Qingmin
authors.initials: Q
authors.lastname: Ruan
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Webber
authors.forename: David G
authors.initials: DG
authors.lastname: Standaert
authors.forename: Julie B
authors.initials: JB
authors.lastname: Olson
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
mesh_terms: D000192:Actinomycetales / Q000378:metabolism; D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004777:Environment; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D011489:Protein Denaturation; D012988:Soil Microbiology; D013302:Streptomyces / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry
chemical_list: D017077:Culture Media, Conditioned; D007976:Leupeptins; D011480:Protease Inhibitors; D051844:alpha-Synuclein; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D004298:Dopamine