Florey Department of Neuroscience and Mental Health - Research Publications

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Generation and analysis of Siah2 mutant mice

Frew, IJ ; Hammond, VE ; Dickins, RA ; Quinn, JMW ; Walkley, CR ; Sims, NA ; Schnall, R ; Della, NG ; Holloway, AJ ; Digby, MR ; Janes, PW ; Tarlinton, DM ; Purton, LE ; Gillespie, MT ; Bowtell, DDL (AMER SOC MICROBIOLOGY, 2003-12)

Siah proteins function as E3 ubiquitin ligase enzymes to target the degradation of diverse protein substrates. To characterize the physiological roles of Siah2, we have generated and analyzed Siah2 mutant mice. In contrast to Siah1a knockout mice, which are growth retarded and exhibit defects in spermatogenesis, Siah2 mutant mice are fertile and largely phenotypically normal. While previous studies implicate Siah2 in the regulation of TRAF2, Vav1, OBF-1, and DCC, we find that a variety of responses mediated by these proteins are unaffected by loss of Siah2. However, we have identified an expansion of myeloid progenitor cells in the bone marrow of Siah2 mutant mice. Consistent with this, we show that Siah2 mutant bone marrow produces more osteoclasts in vitro than wild-type bone marrow. The observation that combined Siah2 and Siah1a mutation causes embryonic and neonatal lethality demonstrates that the highly homologous Siah proteins have partially overlapping functions in vivo.
Very early mobilization following acute stroke: Controversies, the unknowns, and a way forward

Bernhardt, J (WOLTERS KLUWER MEDKNOW PUBLICATIONS, 2008-01)

UNLABELLED: Evidence that organized stroke-unit care results in better outcome has led to positive changes in stroke service delivery around the world. It is well accepted that stroke rehabilitation should commence as early as possible for optimal recovery to be achieved. Exactly how early rehabilitation should start is controversial. Early mobilization (getting up out of bed within 24 h of stroke onset) is a wellestablished feature of acute stroke care in many Scandinavian hospitals. Elsewhere in the world, stroke protocols enforce bed rest for the first few days or foster long periods of bed rest after stroke. This paper aims to provide an overview of the topic of very early mobilization (VEM). It is divided into three sections: section 1 reviews the effects of bed rest and outlines arguments both for and against enforced bed rest after stroke; in section 2, VEM as a treatment for stroke and the limitations of existing literature in the field are described; and section 3 outlines the systematic approach that has been taken by our team of clinical researchers to the study the effect of VEM after stroke. CONCLUSION: VEM represents a simple, easy-to-deliver intervention, requiring little or no equipment. It is potentially deliverable to 85% of the acute stroke population and, if proven to be effective, may help reduce the significant personal and community burden of stroke. As current opinion about when mobilization should begin is divided, one way to move forward is through the conduct of a large high-quality clinical trial (such as A Very Early Rehabilitation Trial (AVERT)). Although some inroads have been made, further research in this field is clearly warranted.
Decline in Physical Fitness From Childhood to Adulthood Associated With Increased Obesity and Insulin Resistance in Adults

Dwyer, T ; Magnussen, CG ; Schmidt, MD ; Ukoumunne, OC ; Ponsonby, A-L ; Raitakari, OT ; Zimmet, PZ ; Blair, SN ; Thomson, R ; Cleland, VJ ; Venn, A (AMER DIABETES ASSOC, 2009-04)

OBJECTIVE: To examine how fitness in both childhood and adulthood is associated with adult obesity and insulin resistance. RESEARCH DESIGN AND METHODS: A prospective cohort study set in Australia in 2004-2006 followed up a cohort of 647 adults who had participated in the Australian Schools Health and Fitness Survey in 1985 and who had undergone anthropometry and cardiorespiratory fitness assessment during the survey. Outcome measures were insulin resistance and obesity, defined as a homeostasis model assessment index above the 75th sex-specific percentile and BMI >or=30 kg/m(2), respectively. RESULTS: Lower levels of child cardiorespiratory fitness were associated with increased odds of adult obesity (adjusted odds ratio [OR] per unit decrease 3.0 [95% CI 1.6-5.6]) and insulin resistance (1.7 [1.1-2.6]). A decline in fitness level between childhood and adulthood was associated with increased obesity (4.5 [2.6-7.7]) and insulin resistance (2.1 [1.5-2.9]) per unit decline. CONCLUSIONS: A decline in fitness from childhood to adulthood, and by inference a decline in physical activity, is associated with obesity and insulin resistance in adulthood. Programs aimed at maintaining high childhood physical activity levels into adulthood may have potential for reducing the burden of obesity and type 2 diabetes in adults.
5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer

Jodrell, DI ; Stewart, M ; Aird, R ; Knowles, G ; Bowman, A ; Wall, L ; Cummings, J ; McLean, C (NATURE PUBLISHING GROUP, 2001-03-02)

PVI 5FU gives increased response rates and reduced toxicity when compared to bolus 5FU (J Clin Oncol 1989, 425-432). PVI 5FU administration was reported to give highly variable (>1000-fold) plasma 5FU concentrations at steady state (FU Css) which correlated with toxicity (Ann Oncol 1996, 47-53); but only 19 patients were studied. Therefore, we performed a study of PVI 5FU in 61 patients with advanced colorectal cancer to assess the variability (inter- and intra-subject) in 5FU Css associated with PVI 5FU (300 mg m(-2)day(-1)) and to attempt to correlate pharmacodynamic end-points (anti-tumour activity, toxicity) with 5FU Css as a prelude to 'exposure-guided' 5FU administration. All 5FU sampling was performed between 10 am and noon. PVI 5FU administration continued to 26 weeks in patients with disease improvement or stabilization. The response rate was 26% (33% stable disease) and median survival was 11 months. Hand-foot syndrome was the most common dose limiting toxicity. Variability in 5FU(300)Css was considerably less than previously reported; 94 +/- 25 ng ml(-1)(CV = 27%). No relationships were demonstrated between subject mean 5FU(300)Css and PD end-points such as response, mucositis, diarrhoea and hand-foot syndrome. The lack of correlation suggests that measurement of 5FU concentrations should not be used to individualize dosing in patients receiving PVI 5FU for advanced colorectal cancer.
Metals and Alzheimer's disease

Adlard, PA ; Bush, AI (IOS PRESS, 2006-11)

There is increasing evidence to support a role for both the amyloid beta-protein precursor (AbetaPP) and its proteolytic fragment, amyloid beta (Abeta), in metal ion homeostasis. Furthermore, metal ions such as zinc and copper can interact with both AbetaPP and Abeta to potentiate Alzheimer's disease by participating in the aggregation of these normal cellular proteins and in the generation of reactive oxygen species. In addition, metal ions may interact on several other AD-related pathways, including those involved in neurofibrillary tangle formation, secretase cleavage of AbetaPP and proteolytic degradation of Abeta. As such, a dysregulation of metal ion homeostasis, as occurs with both aging and in AD, may foster an environment that can both precipitate and accelerate degenerative conditions such as AD. This offers a broad biochemical front for novel therapeutic interventions.
Aβ aggregation and possible implications in Alzheimer's disease pathogenesis

Bharadwaj, PR ; Dubey, AK ; Masters, CL ; Martins, RN ; Macreadie, IG (WILEY, 2009-03)

Amyloid beta protein (Abeta) has been associated with Alzheimer's disease (AD) because it is a major component of the extracellular plaque found in AD brains. Increased Abeta levels correlate with the cognitive decline observed in AD. Sporadic AD cases are thought to be chiefly associated with lack of Abeta clearance from the brain, unlike familial AD which shows increased Abeta production. Abeta aggregation leading to deposition is an essential event in AD. However, the factors involved in Abeta aggregation and accumulation in sporadic AD have not been completely characterized. This review summarizes studies that have examined the factors that affect Abeta aggregation and toxicity. By necessity these are studies that are performed with recombinant-derived or chemically synthesized Abeta. The studies therefore are not done in animals but in cell culture, which includes neuronal cells, other mammalian cells and, in some cases, non-mammalian cells that also appear susceptible to Abeta toxicity. An understanding of Abeta oligomerization may lead to better strategies to prevent AD.
Copper binding to the Alzheimer's disease amyloid precursor protein

Kong, GK-W ; Miles, LA ; Crespi, GAN ; Morton, CJ ; Ng, HL ; Barnham, KJ ; McKinstry, WJ ; Cappai, R ; Parker, MW (SPRINGER, 2008-03)

Alzheimer's disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide called A beta by proteolysis of the precursor protein. APP can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce A beta levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in A beta production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer's disease.
Family clustering of viliuisk encephalomyelitis in traditional and new geographic regions

Vladimirtsev, VA ; Nikitina, RS ; Renwick, N ; Ivanova, AA ; Danilova, AP ; Platonov, FA ; Krivoshapkin, VG ; McLean, CA ; Masters, CL ; Gajdusek, C ; Goldfarb, LG (CENTER DISEASE CONTROL, 2007-09)

Viliuisk encephalomyelitis is an acute, often fatal, meningoencephalitis that tends to develop into a prolonged chronically progressive panencephalitis. Clinical, neuropathologic, and epidemiologic data argue for an infectious cause, although multiple attempts at pathogen isolation have been unsuccessful. To assess mechanisms of disease transmission and spread, we studied 6 multiplex families. Secondary cases occurred among genetically related and unrelated persons in a setting of prolonged intrahousehold contact with a patient manifesting the disease. Transmission to unrelated persons was documented in a densely populated region around the city of Yakutsk in which Viliuisk encephalomyelitis had not been previously known. Initially identified in a small Yakut-Evenk population on the Viliui River of eastern Siberia, the disease subsequently spread through human contacts to new geographic areas, thus characterizing Viliuisk encephalomyelitis as an emerging infectious disease.
An Ancient Duplication of Exon 5 in the Snap25 Gene Is Required for Complex Neuronal Development/Function

Johansson, JU ; Ericsson, J ; Janson, J ; Beraki, S ; Stanic, D ; Mandic, SA ; Wikstrom, MA ; Hokfelt, T ; Ogren, SO ; Rozell, B ; Berggren, P-O ; Bark, C ; Frankel, WN (PUBLIC LIBRARY SCIENCE, 2008-11)

Alternative splicing is an evolutionary innovation to create functionally diverse proteins from a limited number of genes. SNAP-25 plays a central role in neuroexocytosis by bridging synaptic vesicles to the plasma membrane during regulated exocytosis. The SNAP-25 polypeptide is encoded by a single copy gene, but in higher vertebrates a duplication of exon 5 has resulted in two mutually exclusive splice variants, SNAP-25a and SNAP-25b. To address a potential physiological difference between the two SNAP-25 proteins, we generated gene targeted SNAP-25b deficient mouse mutants by replacing the SNAP-25b specific exon with a second SNAP-25a equivalent. Elimination of SNAP-25b expression resulted in developmental defects, spontaneous seizures, and impaired short-term synaptic plasticity. In adult mutants, morphological changes in hippocampus and drastically altered neuropeptide expression were accompanied by severe impairment of spatial learning. We conclude that the ancient exon duplication in the Snap25 gene provides additional SNAP-25-function required for complex neuronal processes in higher eukaryotes.
An investigation of polymorphisms in the 17q11.2-12 CC chemokine gene cluster for association with multiple sclerosis in Australians

Bugeja, MJ ; Booth, D ; Bennetts, B ; Heard, R ; Rubio, J ; Stewart, G (BMC, 2006-07-26)

BACKGROUND: Multiple sclerosis (MS) is a disorder of the central nervous system (CNS) characterised by inflammation and neuronal degeneration. It is believed to result from the complex interaction of a number of genes, each with modest effect. Chemokines are vital to the migration of cells to sites of inflammation, including the CNS, and many are implicated in MS pathogenesis. Most of the CC chemokine genes are encoded in a cluster on chromosome 17q11.2-12, which has been identified in a number of genome wide screens as being potentially associated with MS. METHODS: We conducted a two-stage analysis to investigate the chemokine gene cluster for association with MS. After sequencing the chemokine genes in several DNA pools to identify common polymorphisms, 12 candidate single-nucleotide polymorphisms (SNPs) were genotyped in a cohort of Australian MS trio families. RESULTS: Marginally significant (uncorrected) transmission distortion was identified for four of the SNPs after stratification for several factors. We also identified marginally significant (uncorrected) transmission distortion for haplotypes encompassing the CCL2 and CCL11 genes, using two independent cohorts, which was consistent with recent reports from another group. CONCLUSION: Our results implicate several chemokines as possibly being associated with MS susceptibility, and given that chemokines and their receptors are suitable targets for therapeutic agents, further investigation is warranted in this region.