Overproduction of reactive oxygen species is the primary pathological event related to neuronal cell death in iPSC derived neurons from patients with familial Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease characterised initially loss of dopaminergic neurons in the substantia nigra (SN) and later widespread nondopaminergic neuronal loss including in the cortex. Genetic mutations can cause familial PD, but the sequence of molecular events that trigger neuronal vulnerability is poorly understood. Of the familial forms of PD, point mutations of gene encoding alpha-synuclein (SNCA), the major component of the predominant pathological hallmark called Lewy bodies/neurites, result in dominant PD. To characterize the cellular pathophysiology, we differentiated patient-specific induced pluripotent stem cells (iPSCs) from PD patient fibroblasts carrying alpha-synuclein point mutation, A53T, into functional cortical and midbrain neurons. We demonstrated that endogenous levels of SNCA-A53T reduce cell survival and the source of vulnerability is the excess reactive oxygen species (ROS) evidenced by increased superoxide production and lipid peroxidation levels compared to control. By utilizing the power of patient specific iPSC derived neurons, this study provides an insight into the primary pathological events leading to neuronal cell death and may furthermore be an important direct tool for therapeutic development.