Early Signs of Molecular Defects in iPSC-Derived Neural Stems Cells from Patients with Familial Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, classically associated with extensive loss of dopaminergic neurons of the substantia nigra pars compacta. The hallmark of the disease is the accumulation of pathogenic conformations of the presynaptic protein, alpha-synuclein (alpha Syn), and the formation of intraneuronal protein aggregate inclusions. Neurodegeneration of dopamine neurons leads to a prominent dopaminergic deficiency in the basal ganglia, responsible for motor disturbances. However, it is now recognized that the disease involves more widespread neuronal dysfunction, leading to early and late non-motor symptoms. The development of in vitro systems based on the differentiation of human-induced pluripotent stem cells provides us the unique opportunity to monitor alterations at the cellular and molecular level throughout the differentiation procedure and identify perturbations that occur early, even at the neuronal precursor stage. Here we aim to identify whether p.A53T-alpha Syn induced disturbances at the molecular level are already present in neural precursors. Towards this, we present data from transcriptomics analysis of control and p.A53T-alpha Syn NPCs showing altered expression in transcripts involved in axon guidance, adhesion, synaptogenesis, ion transport, and metabolism. The comparative analysis with the transcriptomics profile of p.A53T-alpha Syn neurons shows both distinct and overlapping pathways leading to neurodegeneration while meta-analysis with transcriptomics data from both neurodegenerative and neurodevelopmental disorders reveals that p.A53T-pathology has a significant overlap with the latter category. This is the first study showing that molecular dysregulation initiates early at the p.A53T-alpha Syn NPC level, suggesting that synucleinopathies may have a neurodevelopmental component.