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Eichelsdoerfer J.L.,California State University, Fullerton | Evans J.A.,California State University, Fullerton | Slaugenhaupt S.A.,Harvard University | Cuajungco M.P.,California State University, Fullerton | Cuajungco M.P.,Mental Health Research Institute
Journal of Biological Chemistry

Chelatable zinc is important in brain function, and its homeostasis is maintained to prevent cytotoxic overload. However, certain pathologic events result in intracellular zinc accumulation in lysosomes and mitochondria. Abnormal lysosomes and mitochondria are common features of the human lysosomal storage disorder known as mucolipidosis IV (MLIV). MLIV is caused by the loss of TRPML1 ion channel function. MLIV cells develop large hyperacidic lysosomes, membranous vacuoles, mitochondrial fragmentation, and autophagic dysfunction. Here, we observed that RNA interference of mucolipin-1 gene (TRPML1) in HEK-293 cells mimics the MLIV cell phenotype consisting of large lysosomes and membranous vacuoles that accumulate chelatable zinc. To show that abnormal chelatable zinc levels are indeed correlated with MLIV pathology, we quantified its concentration in cultured MLIV patient fibroblast and control cells with a spectrofluorometer using N-(6-methoxy-8-quinolyl)-p-toluene sulfonamide fluorochrome. We found a significant increase of chelatable zinc levels in MLIV cells but not in control cells. Furthermore, we quantified various metal isotopes in whole brain tissue of TRPML1-/- null mice and wild-type littermates using inductively coupled plasma mass spectrometry and observed that the zinc-66 isotope is markedly elevated in the brain of TRPML1-/- mice when compared with controls. In conclusion, we show for the first time that the loss of TRPML1 function results in intracellular chelatable zinc dyshomeostasis. We propose that chelatable zinc accumulation in large lysosomes and membranous vacuolesmaycontribute to the pathogenesis of the disease and progressive cell degeneration in MLIV patients. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Stafford L.,Center for Womens Mental Health | Stafford L.,University of Melbourne | Berk M.,University of Melbourne | Berk M.,Australia Orygen Research Center | Berk M.,Mental Health Research Institute
Journal of Clinical Psychiatry

Objective: Depression is associated with immune activation as well as oxidative stress. Statins have in vitro and in vivo antiinflammatory and antioxidative properties. We prospectively investigated whether the use of statins was associated with a reduced risk of development of depression in individuals who have had a cardiac event or intervention. Method: Participants were recruited between May 2005 and March 2006 from the Geelong Hospital, Geelong, Australia, a tertiary hospital in regional Australia that serves a catchment area shown to be representative of the broader Australian community. Patients who were hospitalized for angioplasty, myocardial infarction, or coronary artery bypass graft surgery (N = 193) were followed up prospectively for 9 months to assess development of depression. Depression data were collected 3 months postdischarge (T1) by structured clinical interview (using the Mini International Neuropsychiatric Interview, version 5) and 9 months postdischarge (T2) by self-report (using the Hospital Anxiety and Depression Scale). Major depressive disorder, minor depression, and dysthymia were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Data on statins were collected from medical records. The association between statin therapy and depression was tested using both linear and logistic regression models controlling for clinical, psychological, and demographic confounders. Results: At discharge, 157 participants (81.3%) were receiving statin therapy. Adjusting for possible confounders, taking statins at discharge had a protective effect on depression at T1, reducing the likelihood of dysthymia, minor depression, or major depression by 69% (95% CI, 0.097-0.972; P = .045). At the T2 end point, statin therapy again had a protective effect and was associated with a 79% reduction in the likelihood of depression (95% CI, 0.052-0.876; P = .032). The linear regression model to predict depression at T2 was significantly different from zero (F11,180 = 8.686, P < .001) and explained 36.3% of the variance in depression. Conclusions: The use of statins was associated with significant reduction in the risk of depression in individuals who have had a cardiac event. This supports the role of oxidative and inflammatory processes in depression and opens the door to rational and novel pathophysiologically based therapies distinct from conventional antidepressants. © Copyright 2010 Physicians Postgraduate Press, Inc. Source

Scarr E.,University of Melbourne | Scarr E.,Mental Health Research Institute
CNS Neuroscience and Therapeutics

Phylogenetically, acetylcholine is an ancient neurochemical. Therefore, it is not surprising that cholinergic neurons project extensively throughout the central nervous system, innervating a wide range of structures within the brain. In fact, acetylcholine is involved in processes that underpin some of our most basic central functions. Both muscarinic and nicotinic receptor families, which mediate cholinergic transmission, have been implicated in the pathophysiology of psychiatric and neurological disorders. The question that remains to be definitively answered is whether or not these receptors are viable targets for the development of future therapeutic agents. © 2011 Blackwell Publishing Ltd. Source

Munkholm K.,Copenhagen University | Vinberg M.,Copenhagen University | Berk M.,Deakin University | Berk M.,University of Melbourne | And 2 more authors.
Bipolar Disorders

Objective: Alterations in gene expression in bipolar disorder have been found in numerous studies. It is unclear whether such alterations are related to specific mood states. As a biphasic disorder, mood state-related alterations in gene expression have the potential to point to markers of disease activity, and trait-related alterations might indicate vulnerability pathways. This review therefore evaluated the evidence for whether gene expression in bipolar disorder is state or trait related. Methods: A systematic review, using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline for reporting systematic reviews, based on comprehensive database searches for studies on gene expression in patients with bipolar disorder in specific mood states, was conducted. We searched Medline, Embase, PsycINFO, and The Cochrane Library, supplemented by manually searching reference lists from retrieved publications. Results: A total of 17 studies were included, comprising 565 patients and 418 control individuals. Six studies evaluated intraindividual alterations in gene expression across mood states. Two of five studies found evidence of intraindividual alterations in gene expression between a depressed state and a euthymic state. No studies evaluated intraindividual differences in gene expression between a manic state and a euthymic state, while only one case study evaluated differences between a manic state and a depressed state, finding altered expression in seven genes. No study investigated intraindividual variations in gene expression between a euthymic state and multiple states of various polarities (depressive, manic, hypomanic). Intraindividual alterations in expression of the same genes were not investigated across studies. Only one gene (the brain-derived neurotrophic factor gene; BDNF) was investigated across multiple studies, showing no alteration between bipolar disorder patients and control individuals. Conclusions: There is evidence of some genes exhibiting state-related alterations in expression in bipolar disorder; however, this finding is limited by the lack of replication across studies. Further prospective studies are warranted, measuring gene expression in various affective phases, allowing for assessment of intraindividual differences. © 2012 John Wiley and Sons A/S. Source

Hill R.A.,Mental Health Research Institute | Hill R.A.,University of Melbourne
Journal of Neuroendocrinology

Sex steroid hormones and neurotrophic factors are involved in pruning and shaping the developing brain and have been implicated in the pathogenesis of neurodevelopmental disorders. Sex steroid hormones are also involved in the regulation of brain-derived neurotrophic factor expression. A review of the literature is provided on the relationship between brain-derived neurotrophic factor and sex steroid hormones, as well as the mechanisms behind this interaction, in the context of how this relationship may be involved in the development of neurodevelopmental psychiatric illnesses, such as schizophrenia and depression. © 2012 The Author. Journal of Neuroendocrinology © 2012 British Society for Neuroendocrinology. Source

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