Previous research has demonstrated that mutations in the SCNA gene, a gene responsible for the production of alpha-synuclein, are associated with an aggressive form of Parkinson’s disease. Although it’s known that the aggregation of the toxic phosphorylated alpha-synuclein contributes to neurodegeneration in Parkinson’s, it’s not clear if those toxic clumps occur early or late in the neurodegenerative process.
To help answer this question, researchers used human-induced pluripotent stem cells (hiPSCs) from four patients with Parkinson’s caused by SCNA mutations and seven healthy controls to create midbrain dopaminergic neurons—a type of neuron that experiences early and extensive damage in Parkinson’s disease.
Even before the pluripotent cells developed into dopaminergic neurons, researchers were able to detect increased levels of alpha-synuclein in the SCNA-derived cells compared to the healthy control cells. SCNA-derived cells also contained more and larger alpha-synuclein clumps and demonstrated impaired calcium control, which plays a role in neuronal signaling, compared to healthy control cells.
As the SCNA-derived cells developed further, they continued to form alpha-synuclein aggregates and show impaired calcium flow, but also went on to develop mitochondrial and lysosomal abnormalities, all signs of oxidative stress.
“Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.”