Autism spectrum disorders (ASDs) are multifactorial diseases which affect 1:68 children in the United States alone. Both genetic and environmental components likely contribute to the diverse symptoms of these devastating diseases. For years a significant body of literature has been building characterizing changes in heavy metals and transition metals present in ASD patient blood and tissues. Many metals are foreign and directly toxic in various tissues, but some are important cofactors required for normal biological processes. Nevertheless, even important biometals are also well known to produce adverse developmental effects when present in limiting or excess quantities. Despite the serious physiological consequences of improper metal regulation, there have been few attempts to determine whether changes in metal accumulation actually cause or worsen the neuronal dysfunction found in ASDs. The rigorous experimental analysis required to address these issues is impossible to do in human patients. We are therefore using the powerful genetic system of Drosophila to study brain defects present in one specific ASD, Fragile X Syndrome (FXS). FXS is caused by loss of function of a single gene, FMR1, and is the single leading known genetic cause of autism. Drosophila is an extremely tractable genetic system which has a 15 year proven track record for identifying novel mechanisms underlying FXS. Drosophila is therefore an ideal model to study the intersection of genetic and environmental elements on the etiology of ASDs. Our work will focus on transition metal analysis in the Drosophila FXS model since these tightly regulated elements function directly in normal brain development. We hypothesize that disruption of homeostatic mechanisms controlling transition metal usage in the brain contributes to the underlying cellular defects seen in FXS. We will use the Drosophila system to perform the first in-depth analysis of transition metal composition in an autism model brain. Importantly, as FXS is a developmental disorder, we will assess metal quantities throughout critical periods of development. This will allow us to isolate specific stages of aberrant metal accumulation. We will further exploit this model using transgenic regulators of metal homeostasis so that we may ascertain directly the contributions of these metals to FXS brain dysfunction. Thus, these studies will be the first experimental interrogation into whether or not metals within the brain ar able to affect neuron development in an ASD.
This proposal will determine the ability of metals such as iron to change the development of neurons in the brains of a Fragile X Syndrome model. Learning how metal accumulation is regulated during brain maturation will positively affect public health by opening up new possibilities for the treatment of this disease and other autism related disorders which affect millions of people worldwide.
| Rudisill, Samuel S; Martin, Bradley R; Mankowski, Kevin M et al. (2018) Iron Deficiency Reduces Synapse Formation in the Drosophila Clock Circuit. Biol Trace Elem Res : |
