Characterization of molecular and epigenetic profiles in cell models of neurodegeneration and aging

Parkinson's disease (PD) is the most frequent neurodegenerative disorder after Alzheimer's disease, affecting about 4% of individuals over 80 years of age. Although it is known that advanced age represents one of the main risk factors for the development of PD, the relationship between the molecular alterations that accompany physiological ageing and the alterations that characterize this disease is still poorly understood. In recent years, cellular reprogramming has been used to produce models of several pathologies that affect cellular types that are not easily accessible otherwise. Induced pluripotent stem cells (IPSCs)-derived neurons represent a versatile model for the study of PD pathogenesis since they can be representative of neuronal deterioration, but appropriate experimental models are needed to recapitulate the age-related characteristics of the disease. Our work proposes to explore the relationship between cellular ageing and PD using dopaminergic neurons (DaNs) obtained from iPSC derived from dermal fibroblasts of PD patients (representative of accelerated ageing trajectory) or centenarians (representative of decelerated ageing trajectory). Our results indicated that iPSC-derived DaNs do not present typical disease-associated features until cells are aged in vitro through extensive culturing. Interestingly, centenarians-derived neurons upon in vitro ageing showed a rapid deterioration towards a senescent-like state, similarly to PD-derived ones.