Biology subjects

Roberts, L. D.

Publications and source records attributed to Roberts, L. D..

8 recordsLinked to original sources

bioRxiv2026

Aberrant CD4+ T cell refeeding response impairs neuro-immune crosstalk in Parkinson's disease

T cells modulate disease associated neuroinflammation in Parkinsons disease (PD). We report that circulating CD4+ T cells from people with PD have a dysregulated transcriptional and cytokine response to fasting and refeeding and an altered metabolic profile. The CD4+ T cell secretome mediates a metabolic program in neurons that is impaired in PD, revealing dysfunctional neuro-immune signalling that may contribute to disease pathology.

neuroscience↗

bioRxiv2025

Tissue-specific endothelial cell heterogeneity in human type 2 diabetes

Transcriptomic heterogeneity of microvascular endothelial cells (MVEC) within subcutaneous adipose tissue (SAT) in preclinical models of obesity/type 2 diabetes mellitus (T2DM) is well-established. Here, we examined if such heterogeneity exists between two canonical insulin-target tissues, SAT and skeletal muscle (SkM). Characterisation of SAT and SkM MVEC from humans with T2DM demonstrated that SAT, but not SkM, exhibited cellular stress at transcriptomic, morphological, and protein levels.

cell biology↗

bioRxiv2023

PIEZO1 force sensing controls global lipid homeostasis

How cardiovascular activity beneficially regulates lipid homeostasis is unclear. Here we hypothesise a mechanism in which mechanical force sensed by PIEZO1 ion channels in endothelium links blood flow to lipid regulation. We engineered mice for conditional deletion of PIEZO1 in endothelium and determined consequences for lipid regulation. Prominent are upregulated expression of hepatic Cyp7a1 and intestinal Ldlr genes, which are pivotal in cholesterol catabolism and excretion. Consistent with such regulation is endothelial PIEZO1-dependence of hepatic, intestinal and whole body cholesterol and bile homeostasis. There is organ perfusion-dependent gene regulation via endothelial PIEZO1 and downstream nitric oxide synthase. Endothelial PIEZO1-deleted mice are protected against hyperlipidaemia and ectopic fat deposition. Human PIEZO1 gene variants and a recapitulated human PIEZO1 gain-of-function variant in mice associate with dyslipidaemia. The data suggest lipid-promoting effects of endothelial force sensing and new opportunity for understanding and addressing problems of hyperlipidaemia.

physiology↗

bioRxiv2022

The 5:2 diet does not increase adult hippocampal neurogenesis or enhance spatial memory in mice

New neurones are generated throughout life in the mammalian brain in a process known as adult hippocampal neurogenesis (AHN). Since this phenomenon grants a high degree of neuroplasticity influencing learning and memory and mood related behaviour, identifying factors that regulate AHN may be important for ameliorating age-related cognitive decline and neurodegeneration. Calorie restriction (CR), in the absence of malnutrition, has been shown to enhance AHN and improve hippocampal-dependent memory, mediated by the stomach hormone, ghrelin. Intermittent fasting (IF), a dietary strategy offering more flexibility than conventional CR, also promotes aspects of AHN. The 5:2 diet is a popular form of IF linked to a range of health benefits, however its effects on AHN and spatial memory are not well characterised. We hypothesised that the 5:2 diet would enhance AHN in a ghrelin-dependent manner. To assess this, we used immunohistochemistry to quantify new adult-born neurones and new neural stem cells (NSCs) in the hippocampal DG of adolescent and adult wild-type and mice lacking the ghrelin receptor following six weeks on a 5:2 diet. We report an age-related decline in neurogenic processes and identify a novel role for ghrelin-receptor in regulating the formation of new adult born NSCs in an age-dependent manner. However, the 5:2 diet did not affect new neurone or NSC formation in the DG. Consistent with this finding the 5:2 diet did not alter performance on a spatial learning and memory task. These data suggest that the 5:2 diet used in this study does not increase AHN or improve associated spatial memory function. HighlightsO_LI5:2 diet does not increase adult hippocampal neurogenesis C_LIO_LI5:2 diet does not enhance spatial memory performance C_LIO_LIThere is an age-related decline in adult hippocampal neurogenesis C_LIO_LIGhrelin-receptor regulates new neural stem cell and new neurone number in an age-related manner C_LIO_LIGhrelin-receptor is required for intact spatial memory C_LI

neuroscience↗

bioRxiv2022

Acyl ghrelin attenuates neurochemical and motor deficits in the 6OHDA model of Parkinsons disease

The feeding-related hormone, acyl-ghrelin, protects dopamine neurons in murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-based models of experimental Parkinsons disease (PD). However, the potential protective effect of acyl-ghrelin on substantia nigra pars compacta (SNpc) dopaminergic neurones and consequent behavioural correlates in the more widely used 6-hydroxydopamine (6-OHDA) rat medial forebrain bundle (MFB) lesion model of PD are unknown. To address this question, acyl-ghrelin levels were raised directly by mini-pump infusion for 7-days prior to unilateral injection of 6-OHDA into the MFB with assessment of amphetamine-induced rotations on days 27 and 35, and immunohistochemical analysis of dopaminergic neurone survival. While acyl-ghrelin treatment was insufficient to elevate food intake or body weight, it attenuated amphetamine-induced circling behaviour and SNpc dopamine neurone loss induced by 6-OHDA. These data support the notion that elevating circulating acyl-ghrelin may be a valuable approach to slow or impair progression of neurone loss in PD. HighlightsO_LIAcyl-ghrelin attenuates SNpc dopamine cell loss in rat 6-OHDA-lesion model of PD C_LIO_LIAcyl-ghrelin attenuates motor deficits in rat 6-OHDA-lesion model of PD C_LI

neuroscience↗

bioRxiv2019

The consequences of lipid remodelling of adipocyte cell membranes being functionally distinct from global lipid storage during obesity

Obesity is a complex disorder where the genome interacts with diet and environmental factors to ultimately influence body mass, composition and shape. Numerous studies have investigated how bulk lipid metabolism of adipose tissue changes with obesity, and in particular how the composition of triglycerides (TGs) changes with increased adipocyte expansion. However, reflecting the analytical challenge posed by examining non-TG lipids in extracts dominated by TGs, the glycerophospholipid (PL) composition of cell membranes has been seldom investigated. PLs contribute to a variety of cellular processes including maintaining organelle functionality, providing an optimised environment for membrane-associated proteins and as pools for metabolites (e.g. choline for one-carbon metabolism and for methylation of DNA). We have conducted a comprehensive lipidomic study of white adipose tissue in mice who become obese either through genetic modification (ob/ob), diet (high fat diet) or a combination of the two using both solid phase extraction and ion mobility to increase coverage of the lipidome. Composition changes in seven classes of lipid (free fatty acids, diglycerides, TGs, phosphatidylcholines, lyso-phosphatidylcholines, phosphatidylethanolamines, and phosphatidylserines) correlated with perturbations in one-carbon metabolism and transcriptional changes in adipose tissue. We demonstrate that changes in TGs that dominate the overall lipid composition of white adipose tissue are distinct from diet-induced alterations of PLs, the predominant components of the cell membranes. PLs correlate better with transcriptional and one-carbon metabolism changes within the cell, suggesting the compositional changes that occur in cell membranes during adipocyte expansion have far-reaching functional consequences.

systems biology↗

bioRxiv2018

Circulating unacylated-ghrelin impairs hippocampal neurogenesis and memory in mice and is altered in human Parkinson’s disease dementia

Blood-borne factors regulate adult hippocampal neurogenesis (AHN) and cognition in mammals, albeit via mechanisms that are poorly understood. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in GOAT-/- mice that lack acyl-ghrelin (AG) but have high levels of UAG, were rescued by treatment with AG. This unexpected finding suggests that the post-translational acylation of ghrelin is an important modulator of neurogenesis and memory in adult mammals. To determine whether this paradigm is relevant to humans we analysed circulating AG:UAG levels in Parkinsons disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients and healthy controls. Uniquely, the ratio of plasma AG:UAG was reduced in the PDD cohort and correlated with cognitive performance. Our results identify UAG as a novel regulator of neurogenesis and cognition, and AG:UAG as a circulating diagnostic biomarker of dementia. The findings extend our understanding of adult brain plasticity regulation by circulating factors and suggest that manipulating the post-translational acylation of plasma ghrelin may offer therapeutic opportunities to ameliorate cognitive decline.\n\nHighlightsO_LICirculating UAG impairs markers of neurogenesis and plasticity\nC_LIO_LIGOAT-/-mice have impaired neurogenesis and spatial memory\nC_LIO_LICirculating acyl-ghrelin (AG) rescues spatial memory deficit in GOAT-/-mice\nC_LIO_LICirculating AG:UAG ratio is reduced in Parkinsons disease dementia\nC_LI

neuroscience↗

bioRxiv2017

The small molecule KHS101 induces bioenergetic dysfunction in glioblastoma cells through inhibition of mitochondrial HSPD1

Pharmacological inhibition of uncontrolled cell growth with small molecule inhibitors is a potential strategy against glioblastoma multiforme (GBM), the most malignant primary brain cancer. Phenotypic profiling of the neurogenic small molecule KHS101 revealed the chemical induction of lethal cellular degradation in molecularly-diverse GBM cells, independent of their tumor subtype, whereas non-cancerous brain cells remained viable. Mechanism-of-action (MOA) studies showed that KHS101 specifically bound and inhibited the mitochondrial chaperone HSPD1. In GBM but not non-cancerous brain cells, KHS101 elicited the aggregation of an enzymatic network that regulates energy metabolism. Compromised glycolysis and oxidative phosphorylation (OXPHOS) resulted in the metabolic energy depletion in KHS101-treated GBM cells. Consistently, KHS101 induced key mitochondrial unfolded protein response factor DDIT3 in vitro and in vivo, and significantly reduced intracranial GBM xenograft tumor growth upon systemic administration, without discernible side effects. These findings suggest targeting of HSPD1-dependent oncometabolic pathways as an anti-GBM therapy.

cancer biology↗