Imperial College London

DrStevenMillership

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Teaching Fellow
 
 
 
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s.millership

 
 
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ICTEM buildingHammersmith Campus

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Publications

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16 results found

Ninkina N, Millership SJ, Peters OM, Connor-Robson N, Chaprov K, Kopylov AT, Montoya A, Kramer H, Withers DJ, Buchman VLet al., 2021, β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins., J Biol Chem

Synucleins, a family of three proteins highly expressed in neurons, are predominantly known for the direct involvement of α-synuclein in the aetiology and pathogenesis of Parkinson's and certain other neurodegenerative diseases, but their precise physiological functions are still not fully understood. Previous studies have demonstrated the importance of α-synuclein as a modulator of various mechanisms implicated in chemical neurotransmission, but information concerning the involvement of other synuclein family members, β-synuclein and γ-synuclein, in molecular processes within presynaptic terminals is limited. Here we demonstrated that the vesicular monoamine transporter 2 (VMAT2)-dependent dopamine uptake by synaptic vesicles isolated from the striatum of mice lacking β-synuclein is significantly reduced. Reciprocally, reintroduction, either in vivo or in vitro, of β-synuclein but not α- or γ-synuclein improves uptake by triple α/β/γ-synuclein deficient striatal vesicles. We also showed that the resistance of dopaminergic neurons of the substantia nigra pars compacta (SNpc) to subchronic administration of the Parkinson's disease-inducing prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) depends on the presence of β-synuclein but only when one or both other synucleins are absent. Furthermore, proteomic analysis of synuclein-deficient synaptic vesicles vs those containing only β-synuclein revealed differences in their protein compositions. We suggest that the observed potentiation of dopamine uptake by β-synuclein might be caused by different protein architecture of the synaptic vesicles. It is also feasible that such structural changes improve synaptic vesicle sequestration of 1-methyl-4-phenylpyridinium (MPP+), a toxic metabolite of MPTP, which would explain why dopaminergic neurons expressing β-synuclein and lacking α-synuclein and/or γ-synuclein are resistant t

Journal article

Villanueva-Hayes C, Millership SJ, 2021, Imprinted Genes Impact Upon Beta Cell Function in the Current (and Potentially Next) Generation, FRONTIERS IN ENDOCRINOLOGY, Vol: 12, ISSN: 1664-2392

Journal article

Mousavy Gharavy SN, Owen BM, Millership SJ, Chabosseau P, Pizza G, Martinez-Sanchez A, Tasoez E, Georgiadou E, Hu M, Fine NHF, Jacobson DA, Dickerson MT, Idevall-Hagren O, Montoya A, Kramer H, Mehta Z, Withers DJ, Ninov N, Gadue PJ, Cardenas-Diaz FL, Cruciani-Guglielmacci C, Magnan C, Ibberson M, Leclerc I, Voz M, Rutter GAet al., 2021, Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis, DIABETOLOGIA, Vol: 64, Pages: 850-864, ISSN: 0012-186X

Journal article

Chabosseau P, Rutter G, Millership S, 2021, Importance of both imprinted genes and functional heterogeneity in pancreatic beta cells: is there a link?, International Journal of Molecular Sciences, Vol: 22, ISSN: 1422-0067

Diabetes mellitus now affects more than 400 million individuals worldwide, with significant impacts on the lives of those affected and associated socio-economic costs. Although defects in insulin secretion underlie all forms of the disease, the molecular mechanisms which drive them are still poorly understood. Subsets of specialised beta cells have, in recent years, been suggested to play critical roles in “pacing” overall islet activity. The molecular nature of these cells, the means through which their identity is established and the changes which may contribute to their functional demise and “loss of influence” in both type 1 and type 2 diabetes are largely unknown. Genomic imprinting involves the selective silencing of one of the two parental alleles through DNA methylation and modified imprinted gene expression is involved in a number of diseases. Loss of expression, or loss of imprinting, can be shown in mouse models to lead to defects in beta cell function and abnormal insulin secretion. In the present review we survey the evidence that altered expression of imprinted genes contribute to loss of beta cell function, the importance of beta cell heterogeneity in normal and disease states, and hypothesise whether there is a direct link between the two.

Journal article

Millership SJ, Van de Pette M, Withers DJ, 2019, Genomic imprinting and its effects on postnatal growth and adult metabolism, Cellular and Molecular Life Sciences, Vol: 76, Pages: 4009-4021, ISSN: 1420-682X

Imprinted genes display parent-of-origin-specific expression with this epigenetic system of regulation found exclusively in therian mammals. Historically, defined imprinted gene functions were almost solely focused on pregnancy and the influence on the growth parameters of the developing embryo and placenta. More recently, a number of postnatal functions have been identified which converge on resource allocation, both for animals in the nest and in adults. While many of the prenatal functions of imprinted genes that have so far been described adhere to the "parental conflict" hypothesis, no clear picture has yet emerged on the functional role of imprints on postnatal metabolism. As these roles are uncovered, interest in the potential for these genes to influence postnatal metabolism and associated adult-onset disease outcomes when dysregulated has gathered pace. Here, we review the published data on imprinted genes and their influence on postnatal metabolism, starting in the nest, and then progressing through to adulthood. When observing the functional effects of these genes on adult metabolism, we must always be careful to acknowledge the influence both of direct expression in the relevant metabolic tissue, but also indirect metabolic programming effects caused by their modulation of both in utero and postnatal growth trajectories.

Journal article

Rached M-T, Millership SJ, Pedroni SMA, Choudhury AI, Costa ASH, Hardy DG, Glegola JA, Irvine EE, Selman C, Woodberry MC, Yadav VK, Khadayate S, Vidal-Puig A, Virtue S, Frezza C, Withers Det al., 2019, Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity, Molecular Metabolism, Vol: 20, Pages: 38-50, ISSN: 2212-8778

ObjectiveSympathetic nervous system and immune cell interactions play key roles in the regulation of metabolism. For example, recent convergent studies have shown that macrophages regulate obesity through brown adipose tissue (BAT) activation and beiging of white adipose tissue (WAT) via effects upon local catecholamine availability. However, these studies have raised issues about the underlying mechanisms involved including questions regarding the production of catecholamines by macrophages, the role of macrophage polarization state and the underlying intracellular signaling pathways in macrophages that might mediate these effects.MethodsTo address such issues we generated mice lacking Irs2, which mediates the effects of insulin and interleukin 4, specifically in LyzM expressing cells (Irs2LyzM−/− mice).ResultsThese animals displayed obesity resistance and preservation of glucose homeostasis on high fat diet feeding due to increased energy expenditure via enhanced BAT activity and WAT beiging. Macrophages per se did not produce catecholamines but Irs2LyzM−/− mice displayed increased sympathetic nerve density and catecholamine availability in adipose tissue. Irs2-deficient macrophages displayed an anti-inflammatory transcriptional profile and alterations in genes involved in scavenging catecholamines and supporting increased sympathetic innervation.ConclusionsOur studies identify a critical macrophage signaling pathway involved in the regulation of adipose tissue sympathetic nerve function that, in turn, mediates key neuroimmune effects upon systemic metabolism. The insights gained may open therapeutic opportunities for the treatment of obesity.

Journal article

Millership S, Tunster SJ, Van de Pette M, Choudhury A, Irvine E, Christian M, Fisher AG, John RM, Scott J, Withers DJet al., 2018, Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice, Molecular Metabolism, Vol: 18, Pages: 97-106, ISSN: 2212-8778

ObjectiveImprinted genes are crucial for the growth and development of fetal and juvenile mammals. Altered imprinted gene dosage causes a variety of human disorders, with growth and development during these crucial early stages strongly linked with future metabolic health in adulthood. Neuronatin (Nnat) is a paternally expressed imprinted gene found in neuroendocrine systems and white adipose tissue and is regulated by the diet and leptin. Neuronatin expression is downregulated in obese children and has been associated with stochastic obesity in C57BL/6 mice. However, our recent studies of Nnat null mice on this genetic background failed to display any body weight or feeding phenotypes but revealed a defect in glucose-stimulated insulin secretion due to the ability of neuronatin to potentiate signal peptidase cleavage of preproinsulin. Nnat deficiency in beta cells therefore caused a lack of appropriate storage and secretion of mature insulin.MethodsTo further explore the potential role of Nnat in the regulation of body weight and adiposity, we studied classical imprinting-related phenotypes such as placental, fetal, and postnatal growth trajectory patterns that may impact upon subsequent adult metabolic phenotypes.ResultsHere we find that, in contrast to the lack of any body weight or feeding phenotypes on the C57BL/6J background, deletion of Nnat in mice on 129S2/Sv background causes a postnatal growth restriction with reduced adipose tissue accumulation, followed by catch up growth after weaning. This was in the absence of any effect on fetal growth or placental development. In adult 129S2/Sv mice, Nnat deletion was associated with hyperphagia, reduced energy expenditure, and partial leptin resistance. Lack of neuronatin also potentiated obesity caused by either aging or high fat diet feeding.ConclusionsThe imprinted gene Nnat plays a key role in postnatal growth, adult energy homeostasis, and the pathogenesis of obesity via catch up growth effects, but this role

Journal article

Millership S, Da Silva Xavier G, Choudhury A, Bertazzo S, Chabosseau PL, Pedroni SMA, Irvine E, Montoya A, Faull P, Taylor WR, Kerr-Conte J, Pattou F, Ferrer J, Christian M, John RM, Latreille M, Liu M, Rutter G, Scott J, Withers DJet al., 2018, Neuronatin regulates pancreatic beta cell insulin content and secretion, Journal of Clinical Investigation, Vol: 128, Pages: 3369-3381, ISSN: 0021-9738

Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient-excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.

Journal article

Connor-Robson N, Peters OM, Millership S, Ninkina N, Buchman VLet al., 2016, Combinational losses of synucleins reveal their differential requirements for compensating age-dependent alterations in motor behavior and dopamine metabolism, Neurobiology of Aging, Vol: 46, Pages: 107-112, ISSN: 0197-4580

Journal article

Van De Pette M, Tunster SJ, McNamara GI, Shelkovnikova T, Millership S, Benson L, Peirson S, Christian M, Vidal-Puig A, John RMet al., 2016, Cdkn1c boosts the development of brown adipose tissue in a murine model of Silver Russell syndrome., PLoS Genetics, Vol: 12, ISSN: 1553-7390

The accurate diagnosis and clinical management of the growth restriction disorder Silver Russell Syndrome (SRS) has confounded researchers and clinicians for many years due to the myriad of genetic and epigenetic alterations reported in these patients and the lack of suitable animal models to test the contribution of specific gene alterations. Some genetic alterations suggest a role for increased dosage of the imprinted CYCLIN DEPENDENT KINASE INHIBITOR 1C (CDKN1C) gene, often mutated in IMAGe Syndrome and Beckwith-Wiedemann Syndrome (BWS). Cdkn1c encodes a potent negative regulator of fetal growth that also regulates placental development, consistent with a proposed role for CDKN1C in these complex childhood growth disorders. Here, we report that a mouse modelling the rare microduplications present in some SRS patients exhibited phenotypes including low birth weight with relative head sparing, neonatal hypoglycemia, absence of catch-up growth and significantly reduced adiposity as adults, all defining features of SRS. Further investigation revealed the presence of substantially more brown adipose tissue in very young mice, of both the classical or canonical type exemplified by interscapular-type brown fat depot in mice (iBAT) and a second type of non-classic BAT that develops postnatally within white adipose tissue (WAT), genetically attributable to a double dose of Cdkn1c in vivo and ex-vivo. Conversely, loss-of-function of Cdkn1c resulted in the complete developmental failure of the brown adipocyte lineage with a loss of markers of both brown adipose fate and function. We further show that Cdkn1c is required for post-transcriptional accumulation of the brown fat determinant PR domain containing 16 (PRDM16) and that CDKN1C and PRDM16 co-localise to the nucleus of rare label-retaining cell within iBAT. This study reveals a key requirement for Cdkn1c in the early development of the brown adipose lineages. Importantly, active BAT consumes high amounts of energy to ge

Journal article

Rosell M, Kaforou M, Frontini A, Okolo A, Chan Y-W, Nikolopoulou E, Millership S, Fenech ME, MacIntyre D, Turner JO, Moore JD, Blackburn E, Gullick WJ, Cinti S, Montana G, Parker MG, Christian Met al., 2014, Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, Vol: 306, Pages: E945-E964, ISSN: 0193-1849

Journal article

Millership S, Ninkina N, Rochford JJ, Buchman VLet al., 2013, γ-synuclein is a novel player in the control of body lipid metabolism, Adipocyte, Vol: 2, Pages: 276-280, ISSN: 2162-3945

Journal article

Karra E, Daly OG, Choudhury A, Yousseif A, Millership S, Neary MT, Scott WR, Chandarana K, Manning S, Hess ME, Iwakura H, Akamizu T, Millet Q, Gelegen C, Drew ME, Rahman S, Emmanuel JJ, Williams SCR, Ruther UU, Bruning JC, Withers DJ, Zelaya FO, Batterham RLet al., 2013, A link between FTO, ghrelin and impaired brain food-cue responsivity, Journal of Clinical Investigation

Journal article

Millership S, Ninkina N, Guschina IA, Norton J, Brambilla R, Oort PJ, Adams SH, Dennis RJ, Voshol PJ, Rochford JJ, Buchman VLet al., 2012, Increased lipolysis and altered lipid homeostasis protect  -synuclein-null mutant mice from diet-induced obesity, Proceedings of the National Academy of Sciences, Vol: 109, Pages: 20943-20948, ISSN: 0027-8424

Journal article

Peters OM, Millership S, Shelkovnikova TA, Soto I, Keeling L, Hann A, Marsh-Armstrong N, Buchman VL, Ninkina Net al., 2012, Selective pattern of motor system damage in gamma-synuclein transgenic mice mirrors the respective pathology in amyotrophic lateral sclerosis, Neurobiology of Disease, Vol: 48, Pages: 124-131, ISSN: 0969-9961

Journal article

Anwar S, Peters O, Millership S, Ninkina N, Doig N, Connor-Robson N, Threlfell S, Kooner G, Deacon RM, Bannerman DM, Bolam JP, Chandra SS, Cragg SJ, Wade-Martins R, Buchman VLet al., 2011, Functional Alterations to the Nigrostriatal System in Mice Lacking All Three Members of the Synuclein Family, Journal of Neuroscience, Vol: 31, Pages: 7264-7274, ISSN: 0270-6474

Journal article

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