Publications
160 results found
Beilina A, Rudenko IN, Kaganovich A, et al., 2014, Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease, Proceedings of the National Academy of Sciences, Vol: 111, Pages: 2626-2631, ISSN: 0027-8424
Sastre M, Katsouri L, Birch AM, et al., 2014, Neuroinflammation in Alzheimer’s, Parkinson’s and Huntington’s Diseases, Neuroinflammation and CNS Disorders, Editors: Woodroofe, Amor, Publisher: John Wiley & Sons
Nalls MA, Saad M, Noyce AJ, et al., 2014, Genetic comorbidities in Parkinson's disease, Human Molecular Genetics, Vol: 23, Pages: 831-841, ISSN: 0964-6906
Pienaar IS, Harrison IF, Elson JL, et al., 2013, An animal model mimicking pedunculopontine nucleus cholinergic degeneration in Parkinson’s disease, Brain Structure & Function
A rostral brainstem structure, the pedunculopontine nucleus (PPN), is severely affected by Parkinson’s disease (PD) pathology and is regarded a promising target for therapeutic deep-brain stimulation (DBS). However, understanding the PPN’s role in PD and assessing the potential of DBS are hampered by the lack of a suitable model of PPN degeneration. Rats were rendered Parkinsonian through a unilateral substantia nigra pars compacta (SNpc) stereotaxic injection of the proteasome inhibitor Lactacystin, to investigate whether the lesion’s pathological effects spread to impact the integrity of PPN cholinergic neurons which are affected in PD. At 5 weeks post-surgery, stereological analysis revealed that the lesion caused a 48 % loss of dopaminergic SNpc neurons and a 61 % loss of PPN cholinergic neurons, accompanied by substantial somatic hypotrophy in the remaining cholinergic neurons. Magnetic resonance imaging revealed T2 signal hyper-/hypointensity in the PPN of the injected hemisphere, respectively at weeks 3 and 5 post-lesion. Moreover, isolated PPN cholinergic neurons revealed no significant alterations in key autophagy mRNA levels, suggesting that autophagy-related mechanisms fail to protect the PPN against Lactacystin-induced cellular changes. Hence, the current results suggest that the Lactacystin PD model offers a suitable model for investigating the role of the PPN in PD.
Watts JC, Giles K, Oehler A, et al., 2013, Transmission of multiple system atrophy prions to transgenic mice, Proceedings of the National Academy of Sciences, Vol: 110, Pages: 19555-19560, ISSN: 1091-6490
Prions are proteins that adopt alternative conformations, which become self-propagating. Increasing evidence argues that prions feature in the synucleinopathies that include Parkinson’s disease, Lewy body dementia, and multiple system atrophy (MSA). Although TgM83+/+ mice homozygous for a mutant A53T α-synuclein transgene begin developing CNS dysfunction spontaneously at ∼10 mo of age, uninoculated TgM83+/− mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain α-synuclein prions, we inoculated the TgM83+/− mice with brain homogenates from two pathologically confirmed MSA cases. Inoculated TgM83+/− mice developed progressive signs of neurologic disease with an incubation period of ∼100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83+/+ mice developed neurologic dysfunction in ∼210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated α-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions. The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago.
Harrison IF, Dexter DT, 2013, Epigenetic targeting of histone deacetylase: Therapeutic potential in Parkinson's disease?, PHARMACOLOGY & THERAPEUTICS, Vol: 140, Pages: 34-52, ISSN: 0163-7258
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- Citations: 157
Dexter DT, Jenner P, 2013, Parkinson disease: from pathology to molecular disease mechanisms, FREE RADICAL BIOLOGY AND MEDICINE, Vol: 62, Pages: 132-144, ISSN: 0891-5849
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- Citations: 457
Thomas MG, Saldanha M, Mistry RJ, et al., 2013, Nicotinamide N-methyltransferase expression in SH-SY5Y neuroblastoma and N27 mesencephalic neurones induces changes in cell morphology via ephrin-B2 and Akt signalling, Cell Death and Disease, Vol: 4, Pages: e669-e669
Hurley MJ, Brandon B, Gentleman SM, et al., 2013, Parkinson's disease is associated with altered expression of Ca<sub>V</sub>1 channels and calcium-binding proteins, BRAIN, Vol: 136, Pages: 2077-2097, ISSN: 0006-8950
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- Citations: 115
Harrison IF, Elson JL, Bury A, et al., 2013, Cholinergic Cell Loss And Altered Morphology Accompanied By Structural Changes Affecting The Pedunculopontine Nucleus In The Lactacystin Rat Model Of Parkinson's Disease, Movement Disorders Society Congress 2013
Pichler I, Del Greco M F, Gögele M, et al., 2013, Correction: Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study., PLoS Med, Vol: 10
[This corrects the article on p. e1001462 in vol. 10.].
Klebe S, Golmard J-L, Nalls MA, et al., 2013, The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism., J Neurol Neurosurg Psychiatry, Vol: 84, Pages: 666-673
The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
Dexter D, Ward R, Crichton R, et al., 2013, ALTERED BRAIN IRON HOMEOSTASIS IN PARKINSON'S DISEASE AND THE POTENTIAL FOR IRON CHELATION THERAPY, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 88, Pages: E163-E163, ISSN: 0361-8609
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- Citations: 3
Ward R, Dexter D, Crichton R, 2013, Mechanisms and Metal Involvement in Neurodegenerative Diseases Introduction, MECHANISMS AND METAL INVOLVEMENT IN NEURODEGENERATIVE DISEASES, Editors: Ward, Crichton, Dexter, Publisher: ROYAL SOC CHEMISTRY, Pages: 1-30, ISBN: 978-1-84973-588-9
Dexter DT, 2013, Parkinson's Disease: Involvement of Iron and Oxidative Stress, MECHANISMS AND METAL INVOLVEMENT IN NEURODEGENERATIVE DISEASES, Editors: Ward, Crichton, Dexter, Publisher: ROYAL SOC CHEMISTRY, Pages: 58-79, ISBN: 978-1-84973-588-9
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- Citations: 1
Durrenberger PF, Fernando FS, Magliozzi R, et al., 2012, Selection of novel reference genes for use in the human central nervous system: a BrainNet Europe Study, ACTA NEUROPATHOLOGICA, Vol: 124, Pages: 893-903, ISSN: 0001-6322
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- Citations: 92
Keller MF, Saad M, Bras J, et al., 2012, Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease., Hum Mol Genet, Vol: 21, Pages: 4996-5009
Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.
Ruffmann C, Bravi I, Calboli FCF, et al., 2012, Dementia in Lewy body disorders: clinicopathological correlations in a large sample from the Parkinson's UK Tissue Bank, 16th Congress of the European-Federation-of-Neurological-Societies (EFNS), Publisher: WILEY-BLACKWELL, Pages: 72-72, ISSN: 1351-5101
Crichton RR, Dexter DT, Ward RJ, 2012, Brain iron metabolism and its perturbation in neurological diseases, Metal Ions in Neurological Systems, Pages: 1-15, ISBN: 9783709110003
Enormous advances have been made in the last decade in understanding iron metabolism and iron homeostasis at both the cellular and the systemic level. This includes the identification of genes and proteins involved in iron transport, such as the ferric reductase DcytB, the proton-coupled ferrous (divalent) iron transporter DMT1, the iron exporter ferroportin and the membrane-bound ferroxidase hephaestin. The modulation of their translation by the iron regulatory protein (IRP) system has also been identified together with the impressive signalling cascades involved in regulating the chef d'orchestre of systemic iron homeostasis, hepcidin. However, exactly how the brain regulates fluxes and storage of iron between neurons, oligodendrocytes, astrocytes and microglial cells remains an enigma. In this review we discuss the possible mechanisms which may be involved in the transfer of iron across the blood-brain barrier(BBB), together with the possible role played by astrocytes. The consequences of iron deficiency and iron excess on brain function are described. Finally, various neurodegenerative diseases, where accumulation of iron may be important in the pathogenesis, are presented as well as the possible use of iron chelators to diminish disease progression.
Ward RJ, de Witte P, Lallemand F, et al., 2012, INFLAMMATION IS INDUCED IN BOTH THE PERIPHERY AND SPECIFIC BRAIN REGIONS BY 'BINGE DRINKING' IN ADOLESCENCE, 35th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA), Publisher: WILEY-BLACKWELL, Pages: 332A-332A, ISSN: 0145-6008
Ward RJ, Dexter DT, Crichton RR, 2012, Chelating Agents for Neurodegenerative Diseases, CURRENT MEDICINAL CHEMISTRY, Vol: 19, Pages: 2760-2772, ISSN: 0929-8673
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- Citations: 52
Sadeghian M, Marinova-Mutafchieva L, Broom L, et al., 2012, Full and partial peroxisome proliferation-activated receptor-gamma agonists, but not delta agonist, rescue of dopaminergic neurons in the 6-OHDA Parkinsonian model is associated with inhibition of microglial activation and MMP expression, JOURNAL OF NEUROIMMUNOLOGY, Vol: 246, Pages: 69-77, ISSN: 0165-5728
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- Citations: 40
Hurley MJ, Dexter DT, 2012, Voltage-gated calcium channels and Parkinson's disease, PHARMACOLOGY & THERAPEUTICS, Vol: 133, Pages: 324-333, ISSN: 0163-7258
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- Citations: 31
Pienaar IS, Burn D, Morris C, et al., 2012, Synaptic Protein Alterations in Parkinson's Disease, MOLECULAR NEUROBIOLOGY, Vol: 45, Pages: 126-143, ISSN: 0893-7648
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- Citations: 27
Swingland JT, Durrenberger PF, Reynolds R, et al., 2012, Mean expression of the X-chromosome is associated with neuronal density, FRONTIERS IN NEUROSCIENCE, Vol: 6, ISSN: 1662-453X
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- Citations: 9
Durrenberger PF, Grünblatt E, Fernando FS, et al., 2012, Inflammatory Pathways in Parkinson’s Disease; A BNE Microarray Study, Parkinson's Disease, Vol: 2012, Pages: 1-16, ISSN: 2090-8083
<jats:p>The aetiology of Parkinson's disease (PD) is yet to be fully understood but it is becoming more and more evident that neuronal cell death may be multifactorial in essence. The main focus of PD research is to better understand substantia nigra homeostasis disruption, particularly in relation to the wide-spread deposition of the aberrant protein α-synuclein. Microarray technology contributed towards PD research with several studies to date and one gene,<jats:italic>ALDH1A1</jats:italic>(Aldehyde dehydrogenase 1 family, member A1), consistently reappeared across studies including the present study, highlighting dopamine (DA) metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Neuronal cell death leads to increased inflammation through the activation of astrocytes and microglia. Using our dataset, we aimed to isolate some of these pathways so to offer potential novel neuroprotective therapeutic avenues. To that effect our study has focused on the upregulation of<jats:italic>P2X7</jats:italic>(purinergic receptor P2X, ligand-gated ion channel, 7) receptor pathway (microglial activation) and on the<jats:italic>NOS3</jats:italic>(nitric oxide synthase 3) pathway (angiogenesis). In summary, although the exact initiator of striatal DA neuronal cell death remains to be determined, based on our analysis, this event does not remain without consequence. Extracellular ATP and reactive astrocytes appear to be responsible for the activation of microglia which in turn release proinflammatory cytokines contributing further to the parkinsonian condition. In addition to tackling oxidative stress pathways we also suggest to reduce microglial and endothelial activation to support neuronal outgrowth.</jats:p>
Crichton R, Dexter DT, Ward RJ, 2011, INFLAMMATORY PROCESSES IN NEURODEGENERATIVE DISEASES, ALCOHOL AND ALCOHOLISM, Vol: 46, Pages: 13-13, ISSN: 0735-0414
Ward R, De Witte P, Lallemand F, et al., 2011, BINGE DRINKING INDUCES SIGNIFICANT CHANGES IN THE INNATE IMMUNE SYSTEM, ALCOHOL AND ALCOHOLISM, Vol: 46, Pages: 6-6, ISSN: 0735-0414
Plagnol V, Nalls MA, Bras JM, et al., 2011, A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease, PLOS GENETICS, Vol: 7, ISSN: 1553-7404
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- Citations: 189
Crichton RR, Dexter DT, Ward RJ, 2011, Brain iron metabolism and its perturbation in neurological diseases, MONATSHEFTE FUR CHEMIE, Vol: 142, Pages: 341-355, ISSN: 0026-9247
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- Citations: 9
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