CONCEPT AND OBJECTIVES

 

Overview

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. There is vast evidence that aberrant confirmations of the presynaptic protein alpa-synuclein (ASYN) are associated in the degeneration of neuronal circuits leading to a number of neurodegenerative disorders called synucleinopathies, of which Parkinson disease (PD) is the most prominent one. Deciphering the manner in which aberrant ASYN conformations lead to disease states, and devising therapeutic strategies to counteract these effects represents a major challenge for future research. We have established a network containing both academic and industrial partners utilizing cutting edge technologies to address this challenge. In this interactive intersectoral scientific environment we aim to train several early stage researchers exposing them in the most qualified European ASYN research groups to state of the art methods with practical application to human health. In particular we will examine

(i)                  the detailed structure of various ASYN conformations,

(ii)                whether measurement of such conformations may be used as biomarkers for PD and related diseases,

(iii)               the pathogenic effects of ASYN using sophisticated cellular and animal models,

in these models the pathways involved in neurotoxicity to examine, in combination with screening methods to identify modulators of ASYN function, possible therapeutic targets.

Objectives

ASYN is a predominantly neuronal protein of ascertain function which is closely linked to neurodegenerative brain diseases like PD, collectively termed synucleinopathies. The ASYN protein has the tendency to oligomerize and aggregate, and this process of aggregation may be crucial for its toxicity. Changes responsible for the aberrant protein conformation can occur on the level of the gene, gene-transcription or by post-transcriptional influences. Various cellular and animal models of synucleinopathies have been generated and have shown neuronal and neurological dysfunction. Although, up to now, a consolidation of the different knowledge resources is missing. 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 synucleinopathis. The focus on a single molecule that is involved in multiple diseases is ideally suited for a multidisciplinary approach. The following issues will be addressed:

 

(A)   To detect biomarkers for PD and other synucleinopathies. This will be achieved by developing methods for the detection of soluble intermediate ASYN species, difficult to detect but crucial for the toxicity in different tissues including human body fluids.

(B)  To identify potential therapeutic targets for PD and other synucleinopathies. This will be done by elucidating the process leading to ASYN aggregation within the cells, conferring toxicity, in various settings including in vitro, yeast, neuronal and glial cells, and in vivo.

(C)  To search for novel therapeutic strategies for PD and other synuclienopathies by enhancement of ASYN clearance. Furthermore, we will examine the impact of ASYN on protein degradation pathways, which may be closely linked to its toxicity.

(D)  To develop novel mouse models with a more physiologic expression of ASYN, compared to existing models. But also to examine the involvement of dopamine metabolism in a successfully established model of ASYN-mediated toxicity in the substantia nigra using viral delivery models.

(E)  To develop novel methods for studying alterations of neurotransmission in vivo in response to various ASYN conformations, and to standardize behavioural testing to correlate such changes to measurable behavioural outcomes.

 

Building on the expertise gathered in the NEURASYN network, it is also the objective of NEURASYN to train young researchers to be fully prepared to meet the increasingly demands for multiple skills of the European (scientific) labour market. NEURASYN will implement 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,

scientific in-depth training focused on a specific topic of a PhD thesis and broad spectrum training covering he various sub-disciplines of translational research.