[
Trends Neurosci,
1995]
A range of neuroanatomical results supports the idea that 'save wire' is an organizing principle of brain structure: that the theory of combinatorial optimization of networks applies to the anatomy of the nervous system. In particular, optimization of the placement of components operates at several hierarchical levels in the nervous system, from gross to microscopic anatomy, and from invertebrates to primates. That is, when anatomical positioning of interconnected neural components is treated like a problem of wire minimization in microchip layout, a hypothesis of 'best of all possible brains' is consistent with the observed siting of brains, ganglia, and even somata of individual neurons that minimizes the length of interconnections. In the case of the positioning of ganglia of Caenorhabditis elegans, optimization predictions of one-in-a-million precision can be verified.AD - Committee on History and Philosophy of Science, University of Maryland, College Park 20742, USA.FAU - Cherniak, CAU - Cherniak CLA - engPT - Journal ArticlePT - ReviewPT - Review, TutorialCY - ENGLANDTA - Trends NeurosciJID - 7808616SB - IM
[
Metabolites,
2018]
While progress has been made in discerning genetic associations with Parkinson's disease (PD), identifying elusive environmental contributors necessitates the application of unconventional hypotheses and experimental strategies. Here, we provide an overview of studies that we conducted on a neurotoxic metabolite produced by a species of common soil bacteria, <i>Streptomyces venezuelae (S. ven</i>), indicating that the toxicity displayed by this bacterium causes stress in diverse cellular mechanisms, such as the ubiquitin proteasome system and mitochondrial homeostasis. This dysfunction eventually leads to age and dose-dependent neurodegeneration in the nematode <i>Caenorhabditis elegans</i>. Notably, dopaminergic neurons have heightened susceptibility, but all of the neuronal classes eventually degenerate following exposure. Toxicity further extends to human SH-SY5Y cells, which also degenerate following exposure. Additionally, the neurons of nematodes expressing heterologous aggregation-prone proteins display enhanced metabolite vulnerability. These mechanistic analyses collectively reveal a unique metabolomic fingerprint for this bacterially-derived neurotoxin. In considering that epidemiological distinctions in locales influence the incidence of PD, we surveyed soils from diverse regions of Alabama, and found that exposure to ~30% of isolated <i>Streptomyces</i> species caused worm dopaminergic neurons to die. In addition to aging, one of the few established contributors to PD appears to be a rural lifestyle, where exposure to soil on a regular basis might increase the risk of interaction with bacteria producing such toxins. Taken together, these data suggest that a novel toxicant within the <i>Streptomyces</i> genus might represent an environmental contributor to the progressive neurodegeneration that is associated with PD.