A team of scientists led by The New York Stem Cell Foundations (NYCSF) Research Institute recreated a human stem cell model of Parkinson’s disease in a dish.
The research involved studying a pair of monozygotic twins, one affected and one unaffected by the disease, an unrelated Parkinson’s patient and four healthy control subjects. The team was able to observe the key features of the diseases, specifically the patient’s neuron’s ability to produce dopamine, which is deficient in patients affected by Parkinson’s. The study, recently published in Cell Reports, allowed the group to identify potential strategies for the development of novel Parkinson’s therapies.
Parkinson’s is attributed to a combination of genetic and non-genetic factors and so far there is no completely effective therapy or cure. The disease is known to be moderately heritable, but the mechanisms of inheritance remain poorly understood and sporadic forms of the Parkinson’s are known to be far more common.
DNA mutations resulting in the production of the enzyme glucocerebrosidase (GBA) have been linked to a five-fold greater risk of developing the disease. Despite this, only 30% of individuals with the mutation have been observed to develop Parkinson’s by the age of 80, emphasizing that multiple factors contribute to this disease. To date, there has not been an appropriate model to identify the multiple causes leading to the onset of the disease.
“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,” commented Susan L. Solomon, NYSCF Chief Executive Officer. “Advanced stem cell research techniques allow us to push the boundaries of science and see what actually goes wrong at the cellular level, step by step during the disease process.”
Studying identical twins, both with the GBA mutation, provided a unique opportunity to dissect and evaluate the diverse contributions of the development of Parkinson’s in one twin, and the lack of the disease in the other. The team produced induced pluripotent stem cells (iPSCs) from skin samples of both twins to generate a model of Parkinson’s in a dish, recapitulating the main characteristics of the disease such as dopamine deficiency and the accumulation of Î±-synuclein.
Upon analyzing the models, the group found that the dopaminergic neurons of both twins had a reduced GBA activity, an elevated level of Î±-synuclein and a reduced capacity to synthesize and release dopamine. Furthermore, the iPSC generated neurons from the affected twin had a poor ability to connect with each other, produced less dopamine and had an increased level of monoamine oxidase B (MAO-B). Treating the neurons affected by Parkinson’s with molecules that lowered the activity of MAO-B together with overexpressed GBA resulted in normalized Î±-synuclein and dopamine levels in the cell models, suggesting that such a combination therapy may be possible for the affected twin.
“The subject of Parkinson’s disease discordant twins gave us an incredible opportunity to utilize stem cell models of disease in a dish to unlock some of the biological mechanisms of disease,” explained Dr. Scott Noggle, NYSCF Vice President, Stem Cell Research and The NYSCF — Charles Evans Senior Research Fellow for Alzheimer’s Disease. “Working with these various different groups and scientists added to the depth and value of the research and we hope our findings will be applicable to other Parkinson’s disease patients and other neurodegenerative disorders.”
Sources: Woodard C M, Campos B A, Kuo S-H et al. iPSC-Derived Dopamine Neurons Reveal Differences between Monozygotic Twins Discordant for Parkinson’s Disease. Cell Reports, doi: http://dx.doi.org/10.1016/j.celrep.2014.10.023 (2014) (Epub ahead of print); The New York Stem Cell Foundation press release: http://www.nyscf.org/pdfs2/NYSCF_PR_2014_11_06_PD_Twins_Paper.pdf