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 α-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.

Evolution of metabolomics profile of crab paste during fermentation

“…Obviously, eating spoiled crab paste creates health risks. Furthermore, evidence suggests that the bacterial metabolites may induce the disease (Caldwell et al, 2009;Ray, Martinez, Berkowitz, Caldwell, & Caldwell, 2014). Thus, detailed metabolite compositions are important for its quality and safety.…”

Hypothesis: Bacteria Control Host Appetites

“…There are, therefore, several ways in which bacteria can manipulate their hosts. In addition, a few pioneering studies implicated the gut microbiota in mood disorders and suggested that bacteria have the capacity to manipulate our feelings via, for example, actions exerted on dopamine (42,43) and peptides involved in appetite such as glucagon-like peptide 1 and peptide YY (45). Indeed, it was found that C. jejuni could induce anxiety-like behavior in mice and it was proposed that this involved the vagal pathway (5).…”

“…Bacteria can produce chemicals that affect this reward system. A common soil bacterium, Streptomyces venezuelae, produced a metabolite that, by disrupting the ubiquitin-proteasome system, destroyed dopamine neurones in Caenorhabditis elegans (42); this neurodegeneration was exacerbated by the presence of dopamine. Recently, a role for H. pylori in Parkinsonism has been suggested, following studies that show H. pylori-infected mice are more likely to have lower levels of dopamine in the area of the brain controlling movements (43); it is believed that this has a chemical basis insofar as the effect occurred even when the bacteria were dead.…”

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

“…elegans is also being used to investigate several potential environmental toxicants for their contribution to DA neurodegeneration. Included in these studies is the evaluation of exposures to manganese, uranium, methylmercury (MeHgCl), select botanicals, and bacterially produced secondary metabolites [45][46][47][48][49]. Given the unmet need in understanding environmental contributors to neurodegenerative diseases, the mechanistic capacity, experimental accessibility, and limited regulatory requirements surrounding invertebrate research render C. elegans an attractive system for continued expansion of molecular toxicological analyses.…”

“…A survey of a few worm-to-cell culture translational studies reveals wide ranging fold Ethosuximide 2 mg/ml 30 μg/ml 66X [52] differences between these experimental systems, wherein 0.5× to 160× chemical was used in the C. elegans studies (Table 3). It should be noted, however, that in most of these studies, only a single concentration of chemical was examined in either the worm or cell culture experiments [26,45,54]. Thus, it is likely that the minimum fold difference required for a biological response is not accurately represented in these studies, nor was it the goal for the cited literature.…”