Dottorato in BIOCHIMICA

Titolo della tesi: PARP-1 and Alzheimer’s disease: from molecular functions to biological outcomes in Drosophila melanogaster models

Alzheimer’s disease (AD) is an irreversible age-related neurodegenerative disorder clinically characterized by severe memory impairment, language deficits and cognitive decline. The major neuropathological hallmarks of AD include extracellular deposits of the β-amyloid (Aβ) peptides and cytoplasmic neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. The accumulation of plaques and tangles in the brain triggers a cascade of molecular events that culminate in neuronal damage and cell death. Despite extensive research, our understanding of the molecular basis of AD pathogenesis remains incomplete and a cure for this devastating disease is still not available. A growing body of evidence in different experimental models suggests that poly(ADP-ribose) polymerase-1 (PARP-1) overactivation might be a crucial component of the molecular network of interactions responsible for AD pathogenesis. In this work, genetic, molecular and biochemical approaches were combined to investigate the effects of two different PARP-1 inhibitors (Olaparib and MC2050) in Drosophila models of Alzheimer’s disease by exploring their neuroprotective and therapeutic potential in vivo. Both pharmacological inhibition and genetic inactivation of PARP-1 significantly extend lifespan and improve the climbing ability of transgenic AD flies. Consistently, PARP-1 inhibitors lead to a significant decrease of Aβ42 aggregates and partially rescue the epigenetic alterations associated with AD in the brain. Interestingly, Olaparib and MC2050 also suppress the AD-associated aberrant activation of Transposable Elements in neuronal tissues of AD flies. RNA-seq analyses were performed to compare the expression profile of AD transgenic models and AD PARP-1 depleted flies. The main pathways such as the immune system, proteasome, metabolism and ribosomal biogenesis related to differentially expressed genes were evaluated in order to identify PARP1-mediated gene expression contributing to AD pathology.