Blocking aggregate propagation in neurodegenerative diseases

IMPRiND – Inhibiting Misfolded protein Propagation In Neurodegenerative Diseases – is an international consortium that aims to map and target critical steps in the propagation of misfolded tau and α-synuclein, considered the main culprits of neurodegeneration in Alzheimer's and Parkinson's disease respectively.

IMPRiND is funded jointly by the Horizon2020 Programme of the European Commission, the IMI Initiative, and the Swiss State Secretariat for Education, Research and Innovation (SERI).

A growing body of data indicates that the propagation of pathogenic protein aggregates across neural systems could be mediated by misfolded protein seeds that are released and taken up by anatomically connected neurons causing disruption of their function. Therefore, blocking this process may help arrest the progression of PD and AD.

This requires a pre-clinical stage of development that has yet to be met. First, it requires in-depth understanding of the biophysical nature of disease-relevant misfolded assemblies to enable the development of tractable molecular and cell-based readouts of their seeding, trafficking and clearance that closely resemble key pathogenic steps in the human condition. On the other end, there is a need to study early oligomerisation events and develop assays of oligomer trafficking inside cells.

The combination of such approaches could form the basis of facile, powerful platforms to map in an unbiased fashion key steps in the propagation cycle or toxicity. An important next step in the trajectory to the development of targeted therapeutics is the availability of tools that allow rapid validation of targets in cellular systems that more closely mimic the interconnected networks of the brain.

Currently this is limited to animal models, which develop pathology over several months. This bottleneck could be circumvented by organotypic cultures and iPSC-derived models with fluorescent tags to enable live imaging of propagation between neurons.

Another consideration is the species barrier, which though not substantial, it increases incubation periods and costs and may impact on the extent of neurodegeneration. This can be addressed by the development of humanized models as well as a combination of minimally invasive and/or peripherally accessible readouts that facilitate the more effective use of animals.

Our consortium

The IMPRiND consortium comprises 18 partners in 7 European countries, including universities, research centres, SMEs and pharmaceutical companies

It is uniquely positioned to deliver the project objectives as it combines some of the world-leading laboratories in this area of research with access to state of the art academic and industry facilities. Our expertise spans both Alzheimer and Parkinson diseases, with focused complementary interests in all the relevant areas (e.g. biophysical characterisation of proteopathic assemblies; cellular mechanisms of protein propagation, secretion and degradation; iPSC and organotypic cultures; fly and zebrafish genetics; animal models; drug discovery).
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This project receives funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 116060. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038.