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Synaptic dysfunction in Neurodegenerative Diseases

Periodic Reporting for period 1 - SYNDEGEN (Synaptic dysfunction in Neurodegenerative Diseases)

Reporting period: 2017-01-01 to 2018-12-31

Neurodegenerative diseases (NDDs) are a growing health, social and financial burden on societies but so far preclinical research has not been successful in translating to new therapies that can slow or halt disease progression of NDDs. Alzheimer’s disease (AD), the most common NDD, affects over 5 million Europeans, and costs the EU in excess of 55 billion € per year. Parkinson’s disease (PD) is the most common movement disorder, affecting over 500 000 individuals in Europe. Huntington’s disease (HD) is the most common autosomal dominant inherited NDD with a prevalence of 7 afflicted individuals among 100 000. Currently, these diseases lack a curative treatment. Accumulating evidence points to synapses as sites of early dysfunction and aberrant protein misfolding, aggregation and spread in AD, PD and HD. A key problem in research on NDDs has been that the normal physiological roles at synapses of the aggregation-prone proteins (β-amyloid/amyloid precursor protein, tau, α-synuclein and huntingtin), which are linked pathologically and genetically to these diseases, are not known. Using cutting-edge technologies and multidisciplinary approaches the SYNDEGEN consortium aims to bring together leading experts in the EU to determine the molecular and cellular mechanisms whereby synapses become dysfunctional in AD, PD and HD for the purpose of developing novel therapies.
The goal of the consortium is to train talented young scientists in interdisciplinary, innovative and collaborative research aimed at the development of novel molecular based treatment strategies for these major diseases of ageing. A gap in the training of students in these important diseases is that disease expertise and novel methods to study and pharmacologically target synapses are localized in isolated groups in different locations in the EU. This training programme will be implemented in 6 academic centres and 1 SME representing a comprehensive, highly interactive and multidisciplinary partnership.

The main objectives of the program are:
• Elucidate the molecular and cellular mechanisms whereby aberrant age-related misfolding of disease-linked proteins cause early synaptic dysfunction
• Develop strategies of intervention based on early synaptic dysfunction by modulating the synaptic circuitry and function with pharmacological agents, novel antibodies or genetic treatments
• Innovative training of a next generation of dedicated EU biomedical scientists to develop curative therapies for these major diseases of the brain
The SYNDEGEN Early-Stage Researchers (ESRs) have all be recruited and the two associated milestones have been reached. They all have integrated their local graduate school and received the initial ethical, scientific theoretical and technical trainings necessary for a good PhD start. The ‘List of ESR projects’ (D4.1) has been submitted with a slight in April 2017. The ‘Career Development Plan’ of each ESR has been submitted on January 2019 as part of deliverable D4.6 (Report of the ESR progress reports).
The ESRs have participated to already 5 thematic workshops on specific scientific themes by SYNDEGEN teams. The 5th workshop took place on December 11th, 2018, in coordination with the mid-term meeting in Munich. The scientific theme of this workshop was “In vivo-two photon brain imaging & NDD neuropathology”. A special focus has been given on “Using 2 photon imaging for analysis of kinetic changes in brain of living mice, including dendritic spine plasticity”. These workshops have provided a unique range of theoretical training and hands-on sessions to the ESRs. Together with the annual meetings, these workshops have been a genuine opportunity for ESRs to meet very regularly and create a professional community of young researchers.

Plans for ESR secondments have been updated, some secondments already took place. Deliverables D4.5 and D4.12 ‘Report on secondments’ (Months 12 & 24)’ have been submitted.

Major scientific achievements have already been reached by the ESRs within the 3 scientific Work Packages (WPs 1, 2 &3). Details of the scientific progress (including graphs and pictures) of the ESRs on their PhD projects have been submitted in October 2018 as part of the Mid-term report. Deliverables D4.2 and D4.6 ‘Review of the ESR progress reports (Months 12 & 24)’ have been submitted on time.

The consortium management team is in place and a social media group/intranet has been set up by the students to allow exchange of information, protocols, etc. Associated deliverables (D5.1; D5.2; D5.3 D5.4 and D5.7) have been submitted on time.
Following a pre-kickoff meeting in November 2016, two consequent annual meetings have taken place in June 2017 in Lund and in June 2018 in Göttingen. The mid-term meeting has been organized in Munich on December 10-11th, 2018, as planned.

Scientific dissemination and outreach actions have taken place in 2017 and 2018. They have been listed in different deliverables (D6.1; D6.2; D6.3; D6.4 and D6.5). The exploitation plan has been discussed during the Mid-term meeting with representatives from the European Commission. Deliverable D7.1 ‘Exploitation plan in place’ has been submitted in January 2019.
Progress beyond the state of the art and expected results
Our understanding of aberrant synaptic function and plasticity in NDDs has grown in recent years. Thus, there is a need for disease-specific therapies targeting the pathological changes at the synaptic level. The complexities of AD, PD and HD pathogenesis at synapses represent a major challenge for the translation of new knowledge from bench to the clinic. SYNDEGEN bridges expertise in molecular, cell and synapse biology with expertise in the pathophysiology, drug-development and clinical care of these NDDs. SYNDEGEN immerses talented young scientists in the interdisciplinary pursuit of novel molecular based treatment strategies for these diseases with the belief that exposure to the clinical care of those afflicted by these diseases will further strengthen their commitment to the development of therapies.

Potential Impact
Enhancing the career perspectives and employability of researchers and contribution to their skills development
The SYNDEGEN programme will have a direct impact on the fellows’ careers. Each PhD student needs special training which supplies (i) that required to fit different skills for future neuroscientific research, (ii) common training related to cutting-edge knowledge in neuroscience and neurodegenerative diseases (NDDs), and (iii) soft and professional skills to design and undertake a research career. The SYNDEGEN training programme ensures all key aspects of innovative approaches and techniques in research and skills training as well as exposure to clinical aspects of NDDs.

Contribution to structuring doctoral/early-stage research training at the European level and strengthening European innovation capacity
The diversity of neuroscience, its rapid growth and the notable advances over the past years, means that there is a demand for high-quality young people, and a plethora of career opportunities for people well trained to take advantage of the multi-disciplinary opportunities available. Particularly, the area of NDDs, ageing and synapse research is a rapid growth area that requires new bridges between basic science and clinical research. SYNDEGEN fits into this thinking lineage.