Parkinson’s disease (PD) is a neurodegenerative disease characterized by the progressive and irreversible degeneration of dopaminergic neurons in the nigrostriatal pathway. Evidence suggest that axonal degeneration is an early event in the disease onset, however the molecular mechanisms involved in the pathogenesis of PD still remain unknown. Necroptosis is a programmed form of cell death, which requires the kinase activity of RIPK1, RIPK3 and MLKL to form the necrosome complex. Recent evidence proposed the contribution of necroptosis activation in several neurodegenerative diseases.
This thesis aims to determine the role of necroptosis in axonal degeneration in the 6-OHDA model of PD. We developed a new methodology to evaluate axonal degeneration in the nigrostriatal pathway in 6-OHDA-injected mice. In addition, activation of necroptosis was observed in axonal regions after 6-OHDA damage. To determine the involvement of necroptosis in axonal degeneration, inhibition of RIPK1 and MLKL was evaluated pharmacologically in vitro, and genetically in vivo. In vitro treatment with RIPK1 and MLKL inhibitors showed a protection in neurite degeneration after damage. In vivo analyses using MLKL null mice, showed a decrease in the degeneration of the nigrostriatal pathway and a delay in motor impairment after damage, demonstrating the contribution of MLKL to axonal degeneration and motor capacity.