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Academic-Industrial Training Network on Alpha-Synuclein-related Brain Diseases

Final Report Summary - NEURASYNC (Academic-Industrial Training Network on Alpha-Synuclein-related Brain Diseases)

Academic-Industrial Training Network on Alpha-Synuclein related Brain Diseases (Neurasync)

PROJECT OBJECTIVES
Alpha-synuclein (ASYN) is a predominantly neuronal protein of uncertain function which is closely linked to neurodegenerative brain diseases. Although ASYN was first identified in mammalian systems in amyloid plaques of Alzheimer’s Disease (AD), it soon became clear that ASYN was more closely linked to Parkinson’s Disease (PD). ASYN is the core component of the cytoplasmic Lewy Bodies (LBs) that characterize PD neuropathologically. Importantly, abnormal deposition of ASYN occurs early in the disease process, prior to neuronal dysfunction, and also occurs in other diseases, such as the LB variant of AD, Multiple System Atrophy and dementia with LBs (DLB), collectively termed synucleinopathies. The ASYN-encoding gene was the first to be associated with familial parkinsonism. A number of point mutations and multiplications of the gene locus are directly associated with autosomal dominant PD. The multiplication cases in particular indicate that excess wildtype (WT) ASYN also leads to PD. Even more importantly, among sporadic cases, polymorphisms which influence ASYN transcription confer disease susceptibility, confirming a central role of control of WT ASYN levels in the pathogenesis of both familial and sporadic PD. The ASYN protein has a tendency to oligomerize and aggregate, and this process of aggregation may be crucial for its toxicity. Various cellular and animal models of synucleinopathies have been created and have shown neuronal and neurological dysfunction. Despite these important insights, significant gaps in our understanding of ASYN and its relationship to disease states exist, in large part because each scientist in the field utilizes a restricted panel of techniques, and generalization of the findings is difficult to achieve. We have accordingly assembled a multidisciplinary group of experts in ASYN biology with the aim of advancing the knowledge in the field and ultimately aiding in the management of patients suffering from synucleinopathies. The focus on a single molecule that is involved in multiple diseases is ideally suited for a multidisciplinary approach.
Building on the expertise gathered in the NEURASYNC network, it is also the objective of NEURASYNC to train young researchers to be fully prepared to meet the increasingly demands for multiple skills of the European (scientific) labour market. NEURASYNC has implemented a comprehensive training programme that is composed of four levels:
1) academic and industrial training,
2) training in scientific and complementary skills,
3) local and network wide European training,
4) scientific in-depth training focussed on a specific topic of a PhD thesis and broad spectrum training covering the various sub-disciplines of translational research.

WORK PERFORMED SINCE THE BEGINNING OF THE PROJECT
All partners recruited fellows who enthusiastically worked on their projects and revealed promising results (see below). The first PhDs were already awarded. Scientific needs of the project made it a must to engage in (inter-sectoral) collaborations, e.g. by providing tissues and compounds as well as lab space and technical assistance. Beside their individual projects, all fellows engaged in network-wide training events covering both scientific topics and complementary skill training. A mutual recognition of the training performed was acquired wherever possible.
The Neurasync homepage (www.Neurasync.eu) was established to raise the public awareness of the Neurasync project. This web site also contains internal pages that are used as a teaching and reference tool for the fellows, contain material of the training weeks, annual presentations etc. All partners of the consortium met regularly for presentation of results and fruitful discussions.

MAIN RESULTS ACHIEVED:
The hallmark of Parkinson disease is the presence of Lewy bodies, protein aggregates formed by misfolded species of the presynaptic ASYN. Under physiological conditions, ASYN is a monomer with no apparent native structure, while it assumes a rigid alpha-helical structure in complex with membranes. When aggregated in Lewy bodies, ASYN acquires a fibrillar conformation rich in beta-sheet content. Thus, modifying the aggregation of ASYN should be a useful therapeutic approach in PD. Delineating the structural basis of the ASYN interactions was used as a first step towards the understanding of the molecular mechanisms.
Structure determination of ASYN using NMR revealed that specific aromatic interactions of ASYN with small molecules are central for ligand-mediated inhibition of amyloid formation.
Regarding ASYN-Lipid interaction, we showed that the membrane-binding of ASYN and its induced structural changes of membrane related to the specificity of the lipid environment, using dual polarisation interferometry. Our results further showed that, in human blood plasma, ASYN associates with HDL, that mediates the transport via the blood-brain barrier. This finding offers the possibility to use lipid-bound ASYN as a biomarker for PD.
Although the ASYN burden hypothesis is presently one of the major theories about the pathogenesis of PD, the mechanisms through which ASYN accumulates and exerts its toxic effects remain unknown. To overcome this we have generated and characterised a new animal model with a more physiologic expression of ASYN, namely a new mouse model overexpressing human ASYN under the complete human ASYN promoter using bacterial artificial chromosome. In a mouse model for Lewy Body dementia, we could demonstrate that the cognitive decline might be due to impairment of neurotransmission and synaptic plasticity in the limbic system by distinct ASYN species.
By generation of high-quality AAVs to deliver human ASYN overload to the rodent brain – to measure dose-response dopaminergic cell loss – we contributed to improve methods to detect neurological dysfunction caused by ASYN.
Regarding the pathogenic pathways of ASYN, we could show that both DJ1 and LAMP2a showed neuroprotective actions in both cellular and animal ASYN models. Furthermore, newly identified susceptibility loci for PD were analysed for their molecular pathways.
There are no causal treatments available for Parkinson and other synucleinopathies. Therefore, novel therapeutic strategies need to be developed for these disease states. Using screening strategies in cell models, we could demonstrate a protective role for tyrosine phosphorylation in ASYN pathobiology, that might be a novel target for therapeutic purposes. In addition, we developed a yeast based platform to identify modulators able to interfere with synergistic cytotoxic effects mediated by the interaction of ASYN and tau. This model was used for the identification of both genes and natural extracts able to modulate the observed phenotype. Transgenic mouse lines generated to study the role of Chaperone-mediated-autophagy in the ASYN degradation failed to show both neurodegeneration and a robust phenotype, so contrary to the initial expectations they will not used as in-vivo models for drug screening.

POTENTIAL IMPACT AND USE:
The Neurasnc project educated well-trained young scientists. This does not only apply to the high-ranking PhD theses due to excellent research projects. Together with the inter-sectoral working experience in both academia and industry, a broad-ranging scientific training enabling a look outside the box, and the complementary skill training, the fellows are perfectly prepared to meet the demands of the European job market.
Given the devastating nature of PD and other synucleinopathies and the lack of causal therapies, there is great need for finding effective treatment. Neurasync contributed to this objective with considerable success by deciphering pathological pathways, using newly-developed innovative cellular and animal models and sophisticated tools for analysis. Several promising therapeutic targets were revealed and new biomarkers invented. The Neurasync network significantly increased the collaborations between the partners with a focus on academic-industrial networking.

SOCIO-ECONOMIC IMPACT AND THE WIDER SOCIETAL IMPLICATIONS OF THE PROJECT
Neurodegenerative brain diseases constitute a major health problem in Europe, and their impact on public health and society is increasing with the aging of the population. The Neurasync consortium successfully contributed to the challenge by structural analysis of the ASYN protein, developing novel disease models and new therapeutic approaches. Findings are not only relevant for academic groups working on neurodegeneration, but also for companies engaged in CNS drug discovery. The work provided within Neurasync will impact patients, their families and care-takers significantly, however, would certainly need another 10 years or so to reach the patients. Apart from the scientific results that were presented both to the scientific community and – via the outreach activity – to a wider public, Neurasync succeeded to train 11 promising scientists to meet the challenging demands of the European job market.

CONTACT DETAILS:
University of Tuebingen
Institute for Medical Genetics and Applied Genomics
Research Management
Calwerstrasse 7
72076 Tuebigen, Germany
Phone: 49 7071 29 72191
Fax: 49 7071 29 25061
E-mail: Carola.Reinhard@med.uni-tuebingen.de