Reprogramming cells from Gulf War veterans into neurons to study Gulf War illness

Abstract

Gulf War illness (GWI), which afflicts at least 25% of veterans who served in the 1990-1991 war in the Persian Gulf, is thought to be caused by deployment exposures to various neurotoxicants, including pesticides, anti-nerve gas pills, and low-level nerve agents including sarin/cyclosarin. GWI is a multisymptom disorder characterized by fatigue, joint pain, cognitive problems, and gastrointestinal complaints. The most prominent symptoms of GWI (memory problems, poor attention/concentration, chronic headaches, mood alterations, and impaired sleep) suggest that the disease primarily affects the CNS. Development of urgently needed treatments depends on experimental models appropriate for testing mechanistic hypotheses and for screening therapeutic compounds. Rodent models have been useful thus far, but are limited by their inability to assess the contribution of genetic or epigenetic background to the disease, and because disease-vulnerable proteins and pathways may be different in humans relative to rodents. As of yet, no postmortem tissue from the veterans has become available for research. We are moving forward with a paradigm shift in the study of GWI, which utilizes contemporary stem cell technology to convert somatic cells from Gulf War veterans into pluripotent cell lines that can be differentiated into various cell types, including neurons, glia, muscle, or other relevant cell types. Such cell lines are immortal and will be a resource for GWI researchers to pursue mechanistic hypotheses and therapeutics.

RETRACTED: Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls

“…Increased autoantibodies of biomarkers NFP, tau, tubulin, and MBP, and neuronal cytoskeletal disruptions, including microtubule instability, axonal degeneration, and altered axonal transport, have been found in many cell and animal studies of toxicant-induced models of GWI [ 27 , 42 , 43 , 44 , 45 , 49 , 52 , 53 , 54 ]. We are only aware of the following prior studies, including our prior pilot study, showing increased autoantibodies in much smaller pilot studies of GW veteran blood samples [ 12 , 55 , 56 , 57 , 58 ].…”

RETRACTED: Sex-Based Differences in Plasma Autoantibodies to Central Nervous System Proteins in Gulf War Veterans versus Healthy and Symptomatic Controls

“…Health symptom complaints reported by GW veterans are consistent with sequelae following exposure to pesticides such as organophosphates, pyrethroids, and DEET [ 51 , 64 , 65 ]. Increased autoantibodies against neurofilament, tau, tubulin, and myelin basic proteins, which are biomarkers for myelin and neuronal cytoskeletal disruptions including microtubule instability, axonal degeneration, and altered axonal transport, have been found in many cell and animal studies of toxicant-induced models of GWI [ 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Our results are consistent with previous reports showing increased various autoantibodies in a smaller and then larger study of GW veteran blood samples [ 16 , 19 , 75 , 76 , 77 , 78 ].…”

Pharmacologically increasing microtubule acetylation corrects stress‐exacerbated effects of organophosphates on neurons

“…We used both human and rat neurons as a cross‐validation because rat neurons are more amenable to established microtubule‐related analyses, while human neurons are a better path toward therapy, given that some features of human neurodegeneration are not reflected in rodents . In the future, an even more refined option would be to use induced pluripotent cell lines from the GW veterans themselves, given that genetic and possibly epigenetic factors potentially relevant to disease susceptibility would be preserved . For now, the results on the human cells confirm that, as with the rat neurons, DFP causes a decrease in tubulin acetylation.…”