Background

Today, there is a significant body of evidence to conclude that modifiers of mutant huntingtin (Htt) cytotoxicity in model systems may modify human disease onset and progression, and may therefore constitute promising therapeutic targets for the development of neuroprotective treatments. Huntingtin partner proteins and other proteins involved in cellular maintenance may be strong candidates in this respect.

Proteins do not act alone in the cell: They work as complex and dynamic networks. It is important to analyse HD-relevant information in the context of these gene/protein interaction networks, as this may reveal pivotal disease modifiers and preferred points of therapeutic intervention. In recent years, there has been considerable progress in the execution of genome-scale screens for modifiers of mutant huntingtin toxicity and in the analysis of the large data sets that have been generated. Additionally, several neuroprotective molecules have been identified in model systems, with however the need to elucidate their primary and secondary targets and to prioritise them for preclinical testing. Finally, unbiased genome-wide association studies are being performed to uncover the genetic modifiers of this disease. Therefore, it will be useful to compare these human polymorphism data with biological and chemical data to determine if the two approaches converge onto the same genes and targets.

A major challenge is now to integrate data on genetic and biological modifiers by using network biology approaches to prioritise the best candidate targets and markers. The integrated analysis of neuronal cell responses to the toxic effects of mutant huntingtin will provide strong biological rationales for the modulation of cell death/survival, and will illuminate promising paths to preventive medicine for HD.

Description

The Biological Modifiers and Neuroprevention Working Group aims to improve the HD drug and marker discovery and development processes. The members of the working group contribute with knowledge and data, and collaborate in concerted actions and grant applications. The mode of operation also includes exchange of information with other EHDN working groups (e.g. the Genetic Modifiers, Biomarkers and Neuroprotective Research WGs).

Current projects

The working group focuses on the following topics:

1. Integration of genome-scale information on modification of neurocytotoxicity.
2. Prioritisation of biological modifiers as candidate targets (assessment of disease, drug treatment): rationale, bioinformatic approaches.
3. Target validation based on models of HD pathogenesis and/or human polymorphism data.
4. Neuroprotective drug discovery and development: Chemistry, drug optimisation, drug prioritisation.
5. Funding.

The immediate actions are:

1. To promote the use of network biology to classify and prioritise biological modifiers of mutant Htt cytotoxicity as therapeutic targets or disease markers/modifiers. In this respect, the working group will contribute to target validation and compound development.
2. To uncover and prioritise neuroprotective molecules for evaluation in mice and rats.

Membership

Experts in model organisms, data integration, network biology, cell and mouse genetics, pharmacology, as well as neurobiologists, medicinal chemists, human geneticists and mathematicians are welcome to join our group to discuss their research experience, practice and projects within the framework of concerted actions.

Contact

Lead Facilitator

, Denmark