Exosomal protein deficiencies: how abnormal RNA metabolism results in childhood-onset neurological diseases

The aim of this project is to study and characterize a novel form of RNA related neurological disorder due to dysfunction of a multi-protein complex called the human exosome. The role of the exosome consists of degradation and maturation of RNA. Mutations in the exosome subunit gene EXOSC3 were reported in patients with infantile-onset degeneration of the brainstem and cerebellum and muscle weakness due to spinal motor neuron dysfunction. We have recently identified mutations in EXOSC8, encoding another component of the human exosome, in infants with a similar severe neurological disease. In addition, these children also lose myelin in the brain and spinal cord, which normally coats and insulates nerves and serves to speed up signalling. The severe and isolated neurological symptoms in these children raise the possibility that the exosome is particularly important in neurons; however, there are still many open questions. Combining the data in human cells and zebrafish will enable us to better define the important genes and interacting partners of the exosome. By modifying exosome components or the some of the here identified interacting factors we may discover potential pathways to alter RNA degradation or processing in neurons, which can be further developed as a therapeutic approach in exosomal diseases or in other types of neurodegenerative diseases caused by abnormal RNA function.