Biology subjects

Oxford, J. T.

Publications and source records attributed to Oxford, J. T..

3 recordsLinked to original sources

bioRxiv2026

Spaceflight-relevant microgravity triggers a sublethal Parkinson's-like dopaminergic decline in human neurons and organoids.

Spaceflight stressors may increase Parkinsons disease (PD) risk, but microgravitys specific contribution to human dopaminergic (DA) vulnerability remains undefined. Here, we exposed human iPSC-derived midbrain DA organoids and differentiated SH-SY5Y neurons to simulated microgravity for 72 hours. This exposure reduced neurite outgrowth, eroded DA identity, and activated familial-PD mitochondrial kinases without depleting extracellular dopamine. We observed severe mitochondrial dysfunction--including membrane potential loss and respiratory suppression--coupled with global translational repression. Furthermore, a sublethal, pre-degenerative state emerged, characterized by the selective release of mitochondrial cell-free DNA without apoptotic activation. Proteomic profiling revealed striking convergence with human PD transcriptomes and astronaut blood, highlighting shared suppression of mitochondrial metabolism, ribosomal translation, and altered RNA splicing. Together, these findings establish simulated microgravity as a sufficient, non-toxin trigger of early PD-like DA dysfunction, providing a robust human model for investigating prodromal neurodegeneration.

neuroscience↗

bioRxiv2022

An amino-terminal fragment of apolipoprotein E4 leads to behavioral deficits, increased PHF-1 immunoreactivity, and mortality in zebrafish

Although the increased risk of developing sporadic Alzheimers disease (AD) associated with the inheritance of the apolipoprotein E4 (APOE4) allele is well characterized, the molecular underpinnings of how ApoE4 imparts risk remains unknown. Enhanced proteolysis of the ApoE4 protein with a toxic-gain of function has been suggested and a 17 kDa amino-terminal ApoE4 fragment (nApoE41-151) has been identified in post-mortem human AD frontal cortex sections. Recently, we demonstrated in vitro, exogenous treatment of nApoE41-151 in BV2 microglial cells leads to uptake, trafficking to the nucleus and increased expression of genes associated with cell toxicity and inflammation. In the present study, we extend these findings to zebrafish (Danio rerio), which is an emerging in vivo model system to study AD. Exogenous treatment of nApoE41-151 to 24-hour post-fertilization for 24 hours resulted in significant mortality. In addition, developmental abnormalities were observed following treatment with nApoE41-151 including improper folding of the hindbrain, delay in ear development, deformed yolk sac, enlarged cardiac cavity, and significantly lower heart rates. Decreased presence of pigmentation was noted for nApoE41-151 treated fish compared with controls. Behaviorally, touch-evoked responses to stimulus were negatively impacted by treatment with nApoE41-151. A similar nApoE31-151 fragment that differs by a single amino acid change (C>R) at position 112 had no effects on these parameters under identical treatment conditions. Additionally, triple-labeling confocal microscopy not only confirmed the nuclear localization of the nApoE41-151 fragment within neuronal populations following exogenous treatment, but also identified the presence of tau pathology, one of the hallmark features of AD. Collectively, these in vivo data demonstrating toxicity as well as sublethal effects on organ and tissue development support a novel pathophysiological function of this AD associated-risk factor.

neuroscience↗

bioRxiv2020

Low Intensity Vibration Restores Nuclear YAP Levels and Acute YAP Nuclear Shuttling in Mesenchymal Stem Cells Subjected to Simulated Microgravity

Reducing the bone deterioration that astronauts experience in microgravity requires countermeasures that can improve the effectiveness of rigorous and time-expensive exercise regimens under microgravity. The ability of low intensity vibrations (LIV) to activate force-responsive signaling pathways in cells suggests LIV as a potential countermeasure to improve cell responsiveness to subsequent mechanical challenge. Mechanoresponse of mesenchymal stem cells (MSC) which maintain bone-making osteoblasts is in part controlled by the "mechanotransducer" protein YAP (Yes-associated protein) which is shuttled into the nucleus in response cyto-mechanical forces. Here, using YAP nuclear shuttling as a measure of MSC mechanoresponse, we tested the effect of 72 hours of simulated microgravity (SMG) and daily LIV application (LIVDT) on the YAP nuclear entry driven by either acute LIV (LIVAT) or Lysophosphohaditic acid (LPA), applied at the end of the 72h period. We hypothesized that SMG-induced impairment of acute YAP nuclear entry will be alleviated by daily application of LIVDT. Results showed that while both acute LIVAT and LPA treatments increased nuclear YAP entry by 50% and 87% over the basal levels in SMG-treated MSCs, nuclear YAP levels of all SMG groups were significantly lower than non-SMG controls. Daily dosing of LIVDT, applied in parallel to SMG, restored the SMG-driven decrease in basal nuclear YAP to control levels as well as increased the LPA-induced but not LIVAT-induced YAP nuclear entry over the non-LIVDT treated, SMG only, counterparts. These cell level observations suggest that utilizing daily LIV treatments is a feasible countermeasure for increasing the YAP-mediated anabolic responsiveness of MSCs to subsequent mechanical challenge under SMG.

bioengineering↗