Florey Institute of Neuroscience and Mental Health

Parkville, Australia

Florey Institute of Neuroscience and Mental Health

Parkville, Australia
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News Article | April 17, 2017
Site: www.eurekalert.org

Less than a year after publishing research identifying a single genetic mutation that caused multiple sclerosis (MS) in two Canadian families, scientists at the University of British Columbia have found a combination of two other mutations in another family that made them highly susceptible to the disease. The "double gene" mutation was identified in a large Canadian family with five members diagnosed with MS - all of whom had the DNA abnormality. Two other family members had the same mutation but didn't develop MS, indicating that some other genetic or environmental conditions are still necessary to trigger the disease process. The discovery of this mutation, on top of last year's findings, should help erase doubts that at least some forms of MS are inherited. The prevailing view has been that a combination of many genetic variations causes a slight increase in susceptibility. In this family, individuals with the double gene mutation have about a 7-in-10 chance of developing MS, compared to a 1-in-1,000 risk in the general population. These mutations, described in the journal Human Mutation, impair both immune function and phagocytosis, the process by which cells eliminate debris and pathogens. "This is the first time that problems with phagocytosis have been linked to MS, and provides scientists with a better understanding the disease's origins and targets for developing new treatments," said lead author Carles Vilarino-Guell, an Assistant Professor of Medical Genetics who collaborated with colleagues at Australia's Florey Institute of Neuroscience and Mental Health. The findings also could be used to screen people with a family history of the disease; an individual who was found to have this mutation could be a candidate for early diagnostic imaging long before symptoms appear, or could opt to reduce environmental risks by taking Vitamin D supplements or quitting smoking. MS results from the body's immune system attacking myelin, the fatty material that insulates neurons and enables rapid transmission of electrical signals. When myelin is damaged, communication between the brain and other parts of the body is disrupted, leading to vision problems, muscle weakness, difficulty with balance and coordination, and cognitive impairments. Canada has one of the highest rate of MS in the world, for reasons that elude scientists. The double mutation, unlike the single mutation described last year, leads to the more typical "relapsing-remitting" form of MS, in which the symptoms come and go. These differences in clinical symptoms suggests that different biological processes are responsible for each type of MS, which could explain why treatments for relapsing-remitting patients are ineffective for people with more debilitating, progressive form of the disease. The family with this mutation had donated to a Canadian-wide collection of blood samples from people with MS, begun in 1993 by co-author A. Dessa Sadovnick, a UBC Professor of Medical Genetics and Neurology. The 20-year project, funded by the MS Society of Canada and the Multiple Sclerosis Scientific Research Foundation, has samples from 4,400 people with MS, plus 8,600 blood relatives - one of the largest such biobanks in the world, stored at UBC and Vancouver Coastal Health's Djavad Mowafaghian Centre for Brain Health.

MELBOURNE, Australia & SAN FRANCISCO--(BUSINESS WIRE)--Prana Biotechnology Ltd (ASX:PBT)(NASDAQ:PRAN) today announced a research collaboration with Takeda Pharmaceuticals International, Inc. to study the ability of Prana’s investigational movement disorders compound, PBT434, to slow or prevent neurodegeneration of the gastrointestinal system. One of the important non-motor features of Parkinson’s disease is often the early presentation of severe and disabling impairment of gastrointestinal function. Parkinson’s disease is characterised by the loss of neurons and their networks in the brain and in the gut. The cause of neurodegeneration and gastrointestinal dysfunction in Parkinson’s disease is not known, but the protein alpha-synuclein has been hypothesized to be implicated in this process. Prana recently announced the publication of results with PBT434 demonstrating significant reduction of alpha-synuclein in various pre-clinical models of Parkinson’s disease in the paper entitled, “The novel compound PBT434 prevents iron-mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease” in the peer reviewed journal Acta Neuropathologica Communications *. This paper suggested that PBT434 may reduce the formation of toxic alpha-synuclein fibrils and aggregates, rescue neurons burdened by such toxic forms of alpha-synuclein and restore motor function in animal models. The research collaboration will investigate the ability of investigational compound PBT434 to mitigate gastrointestinal dysfunction; constipation, lowered colon motility and inflammation in mouse models, including an alpha-synuclein transgenic mouse. Associate Professor David Finkelstein, Prana’s Senior Scientific Consultant and Head of the Parkinson’s Disease Laboratory at the Florey Institute of Neuroscience and Mental Health (Melbourne), said: “This early research is important because our major therapeutic objective is to treat these disabling symptoms and provide an early therapeutic intervention for both motor and non-motor Parkinsonian symptoms in patients which may significantly impact on the quality of life.” PBT434 is the first of a new generation of small molecules from the quinazolinone class of drugs that was specifically designed to block the accumulation and aggregation of alpha-synuclein and is expected to begin human testing in a Phase 1 trial later this year. *The peer reviewed article can be accessed from: https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0456-2 About Prana Biotechnology Limited Prana Biotechnology was established to commercialise research into neurodegenerative diseases such as Alzheimer's disease, Huntington disease, and Parkinsonian disease. The Company was incorporated in 1997 and listed on the Australian Stock Exchange in March 2000 and listed on NASDAQ in September 2002. Researchers at prominent international institutions including The University of Melbourne, The Mental Health Research Institute (Melbourne) and Massachusetts General Hospital, a teaching hospital of Harvard Medical School, contributed to the discovery of Prana’s technology. For further information please visit the Company’s web site at www.pranabio.com.

Merson T.D.,Florey Institute of Neuroscience and Mental Health | Bourne J.A.,Monash University
International Journal of Biochemistry and Cell Biology | Year: 2014

Ischaemic stroke is among the most common yet most intractable types of central nervous system (CNS) injury in the adult human population. In the acute stages of disease, neurons in the ischaemic lesion rapidly die and other neuronal populations in the ischaemic penumbra are vulnerable to secondary injury. Multiple parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. Accumulating evidence indicates that cerebral ischaemia initiates an endogenous regenerative response within the adult brain that potentiates adult neurogenesis from populations of neural stem and progenitor cells. A major research focus has been to understand the cellular and molecular mechanisms that underlie the potentiation of adult neurogenesis and to appreciate how interventions designed to modulate these processes could enhance neural regeneration in the post-ischaemic brain. In this review, we highlight recent advances over the last 5 years that help unravel the cellular and molecular mechanisms that potentiate endogenous neurogenesis following cerebral ischaemia and are dissecting the functional importance of this regenerative mechanism following brain injury. This article is part of a Directed Issue entitled: Regenerative Medicine: the challenge of translation. © 2014 Elsevier Ltd. All rights reserved.

Hossain M.A.,Florey Institute of Neuroscience and Mental Health | Wade J.D.,Florey Institute of Neuroscience and Mental Health
Current opinion in chemical biology | Year: 2014

The relaxin subfamily of peptides within the human insulin superfamily consists of seven members including relaxin-2 and relaxin-3. The former is a pleiotropic hormone that is a vasodilator and cardiac stimulant in the cardiovascular system and an antifibrotic agent whereas the latter is primarily a neuropeptide involved in stress and metabolic control. Both possess the unique three-disulfide heterodimeric peptide structure of insulin. Consequently, the synthesis, both chemical and biological, of relaxin-2 and relaxin-3 has long represented a special challenge to further understanding their structural and functional relationships. This review highlights past and recent developments in the use of chemical and recombinant DNA methods of synthesis of these peptides and current resulting knowledge of their biology. Copyright © 2014 Elsevier Ltd. All rights reserved.

Howells D.W.,Florey Institute of Neuroscience and Mental Health | Sena E.S.,University of Edinburgh | Macleod M.R.,University of Edinburgh
Nature Reviews Neurology | Year: 2014

Translational neuroscience is in the doldrums. The stroke research community was among the first to recognize that the motivations inherent in our system of research can cause investigators to take shortcuts, and can introduce bias and reduce generalizability, all of which leads ultimately to the recurrent failure of apparently useful drug candidates in clinical trials. Here, we review the evidence for these problems in stroke research, where they have been most studied, and in other translational research domains, which seem to be bedevilled by the same issues. We argue that better scientific training and simple changes to the way that we fund, assess and publish research findings could reduce wasted investment, speed drug development, and create a healthier research environment. For 'phase III' preclinical studies - that is, those studies that build the final justification for conducting a clinical trial - we argue for a need to apply the same attention to detail, experimental rigour and statistical power in our animal experiments as in the clinical trials themselves. © 2014 Macmillan Publishers Limited. All rights reserved.

Palmer L.M.,Florey Institute of Neuroscience and Mental Health
Brain Research Bulletin | Year: 2014

Neurons have intricate dendritic morphologies which come in an array of shapes and sizes. Not only do they give neurons their unique appearance, but dendrites also endow neurons with the ability to receive and transform synaptic inputs. We now have a wealth of information about the functioning of dendrites which suggests that the integration of synaptic inputs is highly dependent on both dendritic properties and neuronal input patterns. It has been shown that dendrites can perform non-linear processing, actively transforming synaptic input into Na+ spikes, Ca2+ plateau spikes and NMDA spikes. These membrane non-linearities can have a large impact on the neuronal output and have been shown to be regulated by numerous factors including synaptic inhibition. Many neuropathological diseases involve changes in how dendrites receive and package synaptic input by altering dendritic spine characteristics, ion channel expression and the inhibitory control of dendrites. This review focuses on the role of dendrites in integrating and transforming input and what goes wrong in the case of neuropathological diseases. This article is part of a Special Issue entitled 'Dendrites and Disease'. © 2013 Elsevier Inc.

Pekny M.,Gothenburg University | Pekna M.,Florey Institute of Neuroscience and Mental Health
Physiological Reviews | Year: 2014

Astrocytes are the most abundant cells in the central nervous system (CNS) that provide nutrients, recycle neurotransmitters, as well as fulfill a wide range of other homeostasis maintaining functions. During the past two decades, astrocytes emerged also as increasingly important regulators of neuronal functions including the generation of new nerve cells and structural as well as functional synapse remodeling. Reactive gliosis or reactive astrogliosis is a term coined for the mor-phological and functional changes seen in astroglial cells/astrocytes responding to CNS injury and other neurological diseases. Whereas this defensive reaction of astrocytes is conceivably aimed at handling the acute stress, limiting tissue damage, and restoring homeostasis, it may also inhibit adaptive neural plasticity mechanisms underlying recovery of function. Understanding the multifaceted roles of astrocytes in the healthy and diseased CNS will undoubtedly contribute to the development of treatment strategies that will, in a context-dependent manner and at appropriate time points, modulate reactive astrogliosis to promote brain repair and reduce the neurological impairment. © 2014 the American Physiological Society.

Jackson G.D.,Florey Institute of Neuroscience and Mental Health
Nature Reviews Neurology | Year: 2013

A Task Force of the International League Against Epilepsy has proposed a new pathology-based classification of three types of hippocampal sclerosis-the most frequent brain lesion in drug-resistant temporal lobe epilepsy. This classification is designed to be reproducible across centres, thereby aiding communication of histopathological findings. © 2013 Macmillan Publishers Limited.

Rembach A.,Florey Institute of Neuroscience and Mental Health
Nature Reviews Neurology | Year: 2014

Finding a peripheral biomarker for early Alzheimer disease (AD) is a major challenge. A recent study has validated a plasma protein signature that is associated with mild cognitive impairment and AD, and could predict conversion; however, longitudinal cohort studies of presymptomatic individuals are needed to confirm the findings. © 2014 Macmillan Publishers Limited. All rights reserved.

Calamante F.,Florey Institute of Neuroscience and Mental Health | Calamante F.,University of Melbourne
Progress in Nuclear Magnetic Resonance Spectroscopy | Year: 2013

Cerebral perfusion, also referred to as cerebral blood flow (CBF), is one of the most important parameters related to brain physiology and function. The technique of dynamic-susceptibility contrast (DSC) MRI is currently the most commonly used MRI method to measure perfusion. It relies on the intravenous injection of a contrast agent and the rapid measurement of the transient signal changes during the passage of the bolus through the brain. Central to quantification of CBF using this technique is the so-called arterial input function (AIF), which describes the contrast agent input to the tissue of interest. Due to its fundamental role, there has been a lot of progress in recent years regarding how and where to measure the AIF, how it influences DSC-MRI quantification, what artefacts one should avoid, and the design of automatic methods to measure the AIF. The AIF is also directly linked to most of the major sources of artefacts in CBF quantification, including partial volume effect, bolus delay and dispersion, peak truncation effects, contrast agent non-linearity, etc. While there have been a number of good review articles on DSC-MRI over the years, these are often comprehensive but, by necessity, with limited in-depth discussion of the various topics covered. This review article covers in greater depth the issues associated with the AIF and their implications for perfusion quantification using DSC-MRI. © 2013 Elsevier B.V. All rights reserved.

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