Biology subjects

Richardson, D. R.

Publications and source records attributed to Richardson, D. R..

6 recordsLinked to original sources

bioRxiv2026

Loss of inwardly rectifying potassium channel Kir4.2 drives Parkinson's disease-like motor, cognitive and neuropathological features in mice

A critical barrier to therapeutic development in Parkinsons disease (PD) is the lack of endogenous genetic models that spontaneously recapitulate the diseases progressive, anatomically selective nigrostriatal pathology. Genetic studies have linked KCNJ15, encoding the inwardly rectifying potassium channel Kir4.2, to familial PD via a loss-of-function dominant-negative variant; however, its mechanistic role in neurodegeneration remains unexplored. Here, we demonstrate that Kcnj15-/- mice spontaneously develop a progressive PD-like phenotype, exhibiting a "coordination-first" motor syndrome, anxiety-like behavioural changes and spatial memory impairments. Crucially, neuropathology reveals selective degeneration of substantia nigra pars compacta neurons, sparing the ventral tegmental area, with marked microglial hyperactivation and phosphorylated -synuclein accumulation, faithfully recapitulating the topography of human PD. Striatal transcriptomics further reveals upregulation of oligodendrocyte- and myelin-associated genes, implicating compensatory glial remodeling. These findings identify Kir4.2 as a critical homeostatic regulator of nigrostriatal integrity and establish the Kcnj15-/- mouse as a new physiologically accurate and translatable model for PD research.

neuroscience↗

bioRxiv2024

Reduced Proactive and Reactive Cognitive Flexibility in Older Adults Underlies Performance Costs During Dual-Task Walking: A Mobile Brain/Body Imaging (MoBI) Study

Age-related reductions in cognitive flexibility may limit modulation of control processes during systematic increases to cognitive-motor demands, exacerbating dual-task costs. In this study, behavioral and neurophysiologic changes to proactive and reactive control during progressive cognitive-motor demands were compared across older and younger adults to explore the basis for age-differences in cognitive-motor interference (CMI). 19 younger (19 - 29 years old, mean age = 22.84 +/- 2.75 years, 6 male, 13 female) and 18 older (60 - 77 years old, mean age = 67.89 +/- 4.60 years, 9 male, 9 female) healthy adults completed cued task-switching while alternating between sitting and walking on a treadmill. Gait kinematics, task performance measures, and brain activity were recorded using electroencephalography (EEG) based Mobile Brain/Body Imaging (MoBI). Response accuracy on easier trial types improved in younger, but not older adults when they walked while performing the cognitive task. As difficulty increased, walking provoked accuracy costs in older, but not younger adults. Both groups registered faster responses and reduced gait variability during dual-task walking. Older adults exhibited lower amplitude modulations of proactive and reactive neural activity as cognitive-motor demands systematically increased, which may reflect reduced flexibility for progressive preparatory and reactive adjustments over behavioral control.

neuroscience↗

bioRxiv2023

Melanotransferrin Functions as a Pro-Oncogenic WNT Agonist: A Yin-Yang Relationship in Melanoma with the WNT Antagonist and Metastasis Suppressor, NDRG1

A persistent mystery in the melanoma field has been the function of one of the first melanoma tumor antigens characterized, namely p97 (melanotransferrin; MTf). While MTf expression increases melanoma cell proliferation, migration, and tumorigenesis, the molecular mechanism responsible is unknown. On the other hand, N-myc down-stream regulated gene 1 (NDRG1) is a potent metastasis suppressor and WNT antagonist. Expression of NDRG1 in melanoma cells suggests a role in inhibiting metastasis, with this study investigating MTfs role in oncogenic signaling. We demonstrate MTf acts as a pro-oncogenic WNT agonist, which down-regulates NDRG1, while silencing MTf increases NDRG1 expression. In contrast, silencing NDRG1 increases MTf expression. These observations demonstrate a bidirectional negative feedback loop and "Yin-Yang" relationship between MTf and NDRG1. Mechanistically, MTf was directly associated with the WNT co-receptor, lipoprotein-receptor 6 (LRP6), and increased total LRP6 expression, activated p-LRP6 (Ser1490), {beta}-catenin, and activated {beta}-catenin (Ser552) levels, with MTf expression inducing their nuclear accumulation. Additionally, MTf expression increased downstream WNT targets, namely cyclin D1 and c-Myc, with c-Myc down-regulating NDRG1 expression. Silencing c-Myc prevented the Yin-Yang relationship between NDRG1 and MTf, indicating c-Myc played a key role in their inverse regulation. Melanoma patient specimens demonstrated that a low NDRG1/MTf ratio was significantly (p = 0.008) associated with lower survival and metastasis. Chemotherapeutic agents that up-regulated NDRG1 depressed MTf and nuclear LRP6 and potently inhibited melanoma xenograft growth in vivo. This study demonstrates MTf acts as a WNT agonist, with a Yin-Yang relationship being observed with the WNT antagonist, NDRG1.

cancer biology↗

bioRxiv2023

An Innovative Non-Hormonal Strategy Targeting Redox Active Metals to Down-Regulate Estrogen-, Progesterone-, Androgen- and Prolactin-Receptors in Breast Cancer

Estrogen receptor- (ER-) is a key driver of breast cancer (BC) targeted by tamoxifen. However, tamoxifen resistance is a major problem. An important mechanism of resistance is the activation of EGFR/HER2/HER3 signaling and other hormone receptors (androgen receptor (AR), progesterone receptor (PR), prolactin receptor (PRL-R)) that intrinsically activate ER-. Hence, therapeutics targeting multiple receptors, rather than ER- alone, would be extremely useful and may overcome tamoxifen resistance. This study examined the activity of redox-active di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), on the expression and activation of crucial hormone receptors, their co-factors, and key resistance pathways in ER--positive BC. Strikingly, DpC differentially regulated 106 estrogen-response genes with Sankey diagram analysis demonstrating this was linked to decreased mRNA levels of 4 central hormone receptors involved in BC pathogenesis, namely ER, PR, AR, and PRL-R. Mechanistic dissection demonstrated that due to DpC and Dp44mT binding metal ions, these agents caused a pronounced decrease in ER-, AR, PR, and PRL-R protein expression. Ablation of the metal-binding site in the thiosemicarbazone totally prevented its suppressive activity, demonstrating a unique non-hormonal mechanism. DpC and Dp44mT also inhibited EGFR, HER2, and HER3 activation, their downstream signaling, and the expression of co-factors that promote ER- transcriptional activity, including SRC3, NF-{kappa}B p65, and SP1. In vivo, DpC was highly tolerable and effectively inhibited ER--positive BC growth. In conclusion, through a bespoke non-hormonal mechanism targeting redox active metals, Dp44mT and DpC disrupt multiple key inter-receptor interactions between PR, AR, PRL-R, and tyrosine kinases that act with ER- to promote BC, constituting an innovative therapeutic approach.

cancer biology↗

bioRxiv2019

Multi-domain cognitive assessment of male mice reveals whole body exposure to space radiation is not detrimental to high-level cognition and actually improves pattern separation.

Astronauts on interplanetary space missions - such as to Mars - will be exposed to space radiation, a spectrum of highly-charged, fast-moving particles that includes 56Fe and 28Si. Earth-based preclinical studies with mature, \"astronaut-aged\" rodents show space radiation decreases performance in low- and some high-level cognitive tasks. Given the prevalence of touchscreens in astronaut training and in-mission assessment, and the ability of rodent touchscreen tasks to assess the functional integrity of brain circuits and multiple cognitive domains in a non-aversive way, it is surprising the effect of space radiation on rodent touchscreen performance is unknown. To fill this knowledge gap, 6-month-old C57BL/6J male mice were exposed to whole-body space radiation and assessed on a touchscreen battery starting 1-month later. Relative to Sham, 56Fe irradiation did not overtly change performance on tasks of visual discrimination, reversal learning, rule-based, or object-spatial paired associates learning, suggesting preserved functional integrity of supporting brain circuits. Surprisingly, 56Fe irradiation led to better performance on a dentate gyrus-reliant task of pattern separation ability. Irradiated mice discriminated similar visual cues in [~]40% fewer days and [~]40% more accurately than control mice. Improved pattern separation was not touchscreen-, radiation-particle, or neurogenesis-dependent, as both 56Fe and 28Si irradiation led to faster context discrimination (e.g. Sham Block 5 vs. 56Fe Block 2) in a non-touchscreen task and 56Fe led to fewer new dentate gyrus neurons relative to Sham. These data urge revisitation of the broadly-held view that space radiation is detrimental to cognition.\n\nSIGNIFICANCE STATEMENTAstronauts on an interplanetary mission - such as to Mars - will be unavoidably exposed to galactic cosmic radiation, a spectrum of highly-charged, fast-moving particles. Rodent studies suggest space radiation is detrimental to cognition. However, here we show this is not universally true. Mature mice that received whole body exposure to Mars-relevant space radiation perform similarly to control mice on high-level cognitive tasks, reflecting the functional integrity of key neural circuits. Even more surprisingly, irradiated mice perform better than controls in both appetitive and aversive tests of pattern separation, a mission-critical task reliant on dentate gyrus integrity. Notably, improved pattern separation was not touchscreen-, radiation-particle-, or neurogenesis-dependent. Our work urges revisitation of the generally-accepted conclusion that space radiation is detrimental to cognition.

neuroscience↗

bioRxiv2019

Ferrous-glutathione coupling mediates ferroptosis and frailty in Caenorhabditis elegans

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis1, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in the Caenorhabditis elegans model of ageing2. Here we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan in C. elegans. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant ageing rate. Because excess age-related iron elevation in somatic tissue, particularly in brain3-5, is thought to contribute to degenerative disease6, 7, our data indicate that post-developmental interventions to limit ferroptosis may promote healthy ageing.

molecular biology↗