Network of Centres of Excellence in Neurodegeneration (CoEN)
Carbon-Model: Carbon metabolism systems analysis for the identification of diseaseand
patient-specific metabolic and energetic defects in neurodegenerative diseases.
Nerve cells rely heavily on a sufficient supply of carbon sources such as glucose and
amino acids to function, as they are highly specialised cells with limited ability to store
energy. Defects in the supply and/or proper usage of carbon sources have been
identified in several neurodegenerative disorders. These may represent primary,
disease-causing defects, or may critically contribute to disease processes that ultimately
lead to the degeneration of nerve cells. CARBON-MODEL will develop an integrated
platform to pin-point defects in carbon metabolism and energy production in nerve cells.
The approach taken is designed to be applicable to multiple types of neurodegenerative
disorders or individual patient data where new diagnostic, prognostic and stratification
tools are required. CARBON-MODEL will dissect the individual molecular components that
regulate carbon metabolism using preclinical disease models and induced pluripotent
stem cell (iPSC)-derived neurons, and will implement computational approaches to fully
integrate and systematically analyse these data. The CARBON-MODEL systems platform
will enable the development of novel biomarkers for diagnosis and the implementation of
therapeutic approaches that correct or ‘rewire’ disease- or patient-specific metabolic and
energetic defects, using mitochondrial disorders and amyotrophic lateral sclerosis as
Lead Principal Applicant: Jochen H.M. Prehn, Ph.D.
Co-applicants; Niamh M. Connolly, Ph. D. RCSI
Simon Furney, Ph.D., RCSI
Daniele Bano, Ph.D.
Division or department Bonn
Organisation Deutsches Zentrum für Neurodegenerative Erkrankungen e. V.
(DZNE) in der Helmholtz-Gemeinschaft
CoEN Funding partners: SFI and Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Germany
EU Joint Programme – Neurodegenerative Disease Research
Multinational research projects for Pathway Analysis across Neurodegenerative Diseases-
Title of Poject
Systems Analysis of novel small non-coding RNA in neuronal stress responses: towards novel biomarkers and therapeutics for neurodegenerative disorders- RNA-NEURO
Motor neuron disease, frontotemporal dementia (FTD) and Parkinson’s disease (PD) all are disorders that lead to the death of nerve cells. The current project aims to identify the disease-specific ‘fingerprint’ of a new class of molecules. These molecules are linked directly to stress responses in nerve cells and are called ‘small non-coding RNAs’. These are small ribonucleic acids that not directly produce proteins, but rather regulate wider biological functions. Of note, these can be detected in various fluids of the body including blood. By systematically analyzing these molecules, we aim to identify whether the detection of these molecules in blood helps in patient diagnosis. Furthermore, we know that certain patients have a rapid and progressive disease, while in other patients the disease is progressing more slowly. We therefore aim to investigate whether such molecules also provide information regarding disease progression, which is important information for doctors and patients alike. Finally, we will explore the function of these small non-coding RNAs, with the ultimate aim to employ these as novel therapeutics, as they may boost defense mechanisms in nerve cells.
List of Collobaroators
Prof Jochen HM Prehn, Centre for Systems Medicine and Department of Physiology, Royal College of Surgeons in Ireland, Dublin 2, Phone: +353 1 402 2255, Fax: +353 1 402 2447, Email: email@example.com (Partner 1, Coordinator)
Prof Jørgen Kjems, Aarhus University/Interdiscipl. Nanoscience Ctr., DK-8000 Aarhus, Phone: +45 28992086, Fax: +45 8715 0201, firstname.lastname@example.org (Partner 2)
Dr Michael van Es, Department of Neurology & Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Phone: +31-88-7555555, Fax: +31 302542100, Email: M.A.vanEs@umcutrecht.nl (Partner 3)
Dr Giovanni Nardo, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Phone: +39 023901 4272, Fax: +39 023546277, Email: email@example.com (Partner 4)
Prof Ruth Slack, Brain & Mind Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1M 8M5, Phone: +1 613 562-5800 ext. 8458, Fax: +1 613 562-5434, Email: firstname.lastname@example.org (Partner 5)
Prof Mark Helm, Institute of Pharmacy and Biochemistry, Johannes Gutenberg-Universität Mainz, Staudinger Weg 5, D-55128 Mainz, Phone: 49-6131-3925731, Fax 49-6131-3920373, Email: email@example.com (Partner 6)
FutureNeuro brings together internationally recognised neuroscientists, clinical neurologists, geneticists, cell-biologists, analytical and materials chemists from five different third level institutions (RCSI, TCD, UCD, DCU, NUI Galway) as well as a wider network of clinical neurologists and other collaborators based around the country.
As part of a work package 7 of Future Neuro
Aim: To perform a systematic analysis of tiRNA – protein complexes in ALS and Epilepsy models as well as samples from patients. Binding of tiRNA to protein complexes protect tiRNA from degradation and impacts on their stability, detection ability and function. tiRNA may represent novel regulators of protein translation and miRNA function and represent novel therapeutic targets for neurological disorders. The natural spectrum of tiRNA accumulating in ALS and epilepsy is unknown. Using the pre-clinical mouse models of ALS (SOD1 mt, Fus nt, and TDP-43 mt mice) and epilepsy, we will assess tiRNAs and the composition of tiRNA complexes in these animal models. The researcher will profile tiRNA fragments to establish the profile and compostion of tiRNAs.
The EpimiRNA consortium (formed in mid-2012), involving 16 partners from 8 European countries, the USA and Brazil has received €11.5 million funding from the European Union’s Framework Programme 7 to investigate molecular mechanisms, diagnostics and treatments for epilepsy.
The overall objective of the EpimiRNA consortium is to explore the role of microRNAs in the development, treatment and diagnosis of temporal lobe epilepsy. Scientists will undertake the first complete analysis of microRNA changes across multiple epilepsy models and human brain tissue to identify the active or missing microRNAs in epilepsy. Experiments will then uncover the targets of these microRNAs and, using the latest computer and mathematical modelling techniques, explain how they influence brain excitability. We will look at the genetic code in patients with temporal lobe epilepsy to see if variation or errors may be changing which microRNAs are present in the brain. We will target microRNAs using gene therapy and other approaches and we will search chemical libraries for new compounds which might affect microRNA levels in cells. Seizures or the injuries that trigger epilepsy may cause the release of tiny amounts of microRNA into the bloodstream which can be detected with very sensitive machines. Clinical trials will therefore look at microRNA levels in blood samples from patients. This may lead to non-invasive tests to help doctors predict who may develop epilepsy or respond best to a particular treatment.
Jochen Prehn and the Centre for Systems Medicine are contributing to EpimiRNA with expertise in Systems biology. These approaches are increasingly required to tackle the complex regulation of biological function and disease processes by miRNA. miRNA target multiple mRNA, and each mRNA can be targeted by several miRNA. Recognizing this complexitiy, it is essential to integrate information on miRNA and their mRNA/protein targets as well as spatio-temporal data in the brain. This workpackage will establish an integrative computational model that allows the miRNA and target data to undergo mechanistic analysis, prediction testing, and simulation of effects on neuronal excitability.
The Consortium is coordinated by Professor David Henshall, Royal College of Surgeons in Ireland with Professor Felix Rosenow at Philipps University Marburg (Germany) as Co-coordinator , with the following partners: Professors Jochen Prehn, Gianpierro Cavalleri and Norman Delanty also from the RCSI in Dublin, Professors Gerhard Schratt, Carsten Culmsee and Rainer Schwarting and Karl M. Klein PhD at Philipps University Marburg (Germany), Prof. Jeroen Pasterkamp at the University Medical Center Utrecht (Netherlands), Dr Stephanie Schorge at University College London (U.K.), Prof. Paolo Fabene at the University of Verona (Italy), Prof. Hajo Hamer at Friedrich-Alexander Universität Erlangen/Nuernberg (Germany), Prof. David Goldstein at Duke University (U.S.A.), Prof. Iscia Lopes-Cendes at University of Campinas (Brazil), Prof. Jorgen Kjems at Aarhus University (Denmark) and Prof. Jens Andersen at University of Southern Denmark (Denmark).
The consortium is accompanied by experienced companies: DIXI Microtechniques (France), Cerbomed GmbH (Germany), InteRNA Technologies (Netherlands), Bicoll GmbH (Germany-China), BC Platforms (Finland) and GABO:mi (Germany).
This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant
See the video where Prof David Henshall is speaking about this project
|A combined in vitro single-cell imaging and computational analysis approach to determine and therapeutically target the control principles of neuronal bioenergetics during epilepsy
Glutamate is the main excitatory neurotransmitter in the CNS. Glutamate receptor activation imposes a significant work load on neurons which necessitates an increase in ATP production. However, excessive activation of glutamate receptors promotes neuronal dysfunction and death through glutamate excitotoxicity. Interestingly, neuronal excitation and glutamate toxicity can be substantially modulated by and neuronal bioenergetics using a combined mathematical modelling and single cell imaging approach.