PHENOTYPING CELLULAR DYSHOMEOSTASIS IN CHROMOSOME 8P DISORDER

Chromosome 8p rearrangements lead to a group of rare diseases characterised by neurodevelopmental delays starting early in childhood and progressing with clinical manifestations of varied severity affecting both motor and cognitive abilities.
Given the low incidence of the conditions and the variation in the chromosomal rearrangements, there is currently little information about the disease mechanisms, and it is difficult to generalise information from one case to the next. Moreover, the cellular imbalances associated with the disease are virtually unknown. This impacts directly on the ability to address the condition and to provide appropriate therapeutic approaches.
Working with the Project 8p Foundation, we have uncovered the cellular imbalances that are present in fibroblasts from 8p patients, and we have established that several cellular compartments and homeostasis processes are impaired. These include the mitochondria and lysosomal networks, DNA damage and repair mechanisms, as well as response to cell death challenges and increased senescence. The multiple layers of cellular dyshomeostasis converge towards increased senescence susceptibility, providing targetable pathways to improve the disease phenotypes.