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Synaptic dysfunction in Neurodegenerative Diseases

Periodic Reporting for period 2 - SYNDEGEN (Synaptic dysfunction in Neurodegenerative Diseases)

Reporting period: 2019-01-01 to 2021-06-30

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 disease progression of NDDs. Alzheimer’s disease (AD) affects over 5 million Europeans, and costs the EU in excess of 55 billion € per year. Parkinson’s disease (PD) is affecting over 500 000 individuals in Europe. Huntington’s disease (HD) has 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, which are linked pathologically and genetically to these diseases, are not known. 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. 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 associated milestones have been reached and submitted. All ESRs have integrated their local graduate school and received the initial ethical, scientific theoretical and technical trainings necessary for a good PhD start.
The SynDegen ESRs have participated to 7 thematic workshops on specific scientific themes, conferences and hands-on sessions provided by the SynDegen teams. In 2019, the 6th workshop took place on June 26-28, in coordination with the 3rd SynDegen annual meeting in Bordeaux. Because of the COVID pandemic, no workshop has taken place in 2020. The last training workshop, organized by the Cambridge team, took place by web conferencing on March 29, 2021 - " Clinical and molecular features of neurodegenerative diseases with tau and alpha-synuclein aggregates". The program included 5 keynote lectures with leading experts. Two ‘meeting the patient’ sessions have been organized with patients with tauopathies and a patient diagnosed at age 33 with Parkinson’ Disease. All SYNDEGEN ESRs were present, as well as 75 participants from the SYNDEGEN partner institutes. 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 following the Mid-term meeting. Unfortunately, in 2020 and 2021, most of the planed secondments have been cancelled by the lockdowns in Europe and travel restrictions linked to COVID-19 pandemic.

Major scientific achievements have been reached by the ESRs within the 3 scientific Work Packages (WPs 1, 2 & 3). Details of the scientific progress of the ESRs on their PhD projects are given in the 54 Months periodic report. All scientific deliverables have been submitted. Ten publications have been published by SYNDEGEN ESRs. 20 posters and 6 talks have been presented by the ESRs at national and international conferences.

The kick-off, 2nd and 3rd annual meetings have taken place. The mid-term meeting has been organized in Munich on December 10-11th, 2018, as planned. Due to the COVID-19 pandemic, the final annual meeting has taken place by video conference on June 23rd, 2021. The 24M, 36M and 54M ESR progress reports have been submitted on time.

Scientific dissemination and outreach actions have taken place in 2017, 2018, 2019, 2020 and 2021 (slightly reduced because of the COVID). They have been listed in different deliverables (D6.1 D6.2 D6.3 D6.4 D6.5 D6.8 D6.6 D6.7) which have been submitted on time.

The exploitation plan has been discussed during the Mid-term meeting with representatives from the European Commission. An updated version of the reports on exploitation and IPR activities (M54) have been submitted on time.
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.
Syndegen Consortium