‘RARE MAPS’ aimed to address the challenge of investigating disease mechanisms for rare genetic neurological disorders. In Europe, rare diseases are those that affect less than 1 in 2000 people. However, the existence of up to 8000 different rare (mostly genetic) diseases means that collectively they are anything but rare; around 30 million people are estimated to suffer from a rare disease in Europe alone. This creates a huge medical burden, as most rare diseases have no known effective treatment. The bottleneck in developing targeted therapies is in understanding the underlying mechanisms of diseases at a cellular level. This is particularly challenging for neurological diseases, because the affected tissue (the nervous system) is inaccessible and difficult to model in the lab. Thus, it is important to develop new approaches to systematically study rare disease pathology.
The overarching goal of RARE MAPS is to develop a mechanistic discovery pipeline that can be widely applied to rare neurological disorders. To do this, RARE MAPS proposed to combine disease modelling using human induced pluripotent stem cells (hiPSCs) with a spatial proteomics method called ‘Dynamic Organellar Maps’ (DOMs), to understand how proteins within neurons are altered during disease. hiPSCs are cells that can differentiate into any cell type of the human body, including neurons. Gene editing technology can be used to introduce genetic mutations into hiPSCs, which can then be differentiated into neurons, providing a model of neurological disease in a dish. The DOMs method is then applied to reveal differences between healthy and diseased neurons, by providing information on the identity, quantity and localisation of proteins within the cell. Protein localisation is critical for protein function; cells consist of different membrane-bound compartments called organelles and proteins must be in the correct place to perform their function. Protein trafficking pathways make sure that proteins get to the right destinations. The importance of these pathways is highlighted by the fact that common neurological diseases, e.g. Parkinson’s disease, involve defects in protein trafficking.
Many rare genetic neurological disorders are also caused by problems with protein trafficking, for example, the childhood neurodegenerative disease, AP-4 deficiency syndrome. AP-4 deficiency syndrome is a form of hereditary spastic paraplegia, caused by mutations in a set of genes that create a protein complex called AP-4, which is required for protein trafficking. Using AP-4 deficiency syndrome as a test-case, the main objectives of RARE MAPS were: 1) to establish the DOMs approach in hiPSC-derived neurons; 2) to apply DOMs to study protein trafficking defects in whole brain tissue; 3) to investigate the mechanisms leading to AP-4 deficiency syndrome. The action was successful in meeting its objectives, leading both to the development of methods that can be widely used to study neurological disease, as well as to an increased understanding of the protein mislocalisation events that contribute to disease caused by AP-4 deficiency.
