Researchers have successfully created a human stem cell disease model of Parkinson's disease in a dish.
Scientists led by The New York Stem Cell Foundation (NYSCF) Research Institute studied a pair of identical (monozygotic) twins, one affected and one unaffected with Parkinson's disease, another unrelated Parkinson's patient, and four healthy control subjects.
They were able to observe key features of the disease in the laboratory, specifically differences in the patients' neurons' ability to produce dopamine, the molecule that is deficient in Parkinson's disease.
Parkinson's disease is moderately heritable, but the mechanisms of this inheritance are not well understood.
"The unique scenario of identical twins, one with this disease and one without, allowed our scientists an unprecedented look into the mechanisms of Parkinson's disease," said Susan L Solomon, NYSCF Chief Executive Officer.
DNA mutations resulting in the production of a specific enzyme called glucocerebrosidase (GBA) have been linked to a five-fold greater risk of developing Parkinson's disease; however, only 30 per cent of individuals with this mutation have been shown to develop Parkinson's disease by the age of 80.
This discordance suggests that multiple factors contribute to the development of Parkinson's disease, including both genetic and non-genetic factors.
To date, there has been no appropriate model to identify and test multiple triggers leading to the onset of the disease.
In the study, published in journal Cell Reports, a set of identical twins, both with a GBA mutation, provided a unique opportunity to evaluate and dissect the genetic and non-genetic contributions to the development of Parkinson's disease in one twin, and the lack of disease in the other.
The scientists made induced pluripotent stem (iPS) cells from skin samples from both twins to generate a cellular model of Parkinson's in a dish, recapitulating key features of the disease, specifically the accumulation of alpha-synuclein and dopamine deficiency.
Upon analysing the cell models, the scientists found that the dopamine-producing neurons from both twins had reduced GBA enzymatic activity, elevated alpha-synuclein protein levels, and a reduced capacity to synthesise and release dopamine.
In comparison to his unaffected brother, the neurons generated from the affected twin produced less dopamine, had higher levels of an enzyme called monoamine oxidase B (MAO-B), and poor ability to connect with each other.
Treating the neurons with molecules that lowered the activity of MAO-B together with overexpressed GBA normalised alpha -synuclein and dopamine levels in the cell models.
This suggests that a combination therapy for the affected twin may be possible by simultaneously targeting these two enzymes.
The study was published in the journal Cell Reports.
