A new study on mitochondrial deficits in iPSC-derived nerve cells, funded by the National Institutes of Health and published in Science Translational Medicine, shows that patient-derived stem cells cause different responses to cells from patients with different Parkinson’s etiologies. The study suggests that Parkinson’s intervention may one day be tailored to individuals based on the genetic cause of their illness.
Parkinson’s disease is a debilitating disease that affects multiple regions of the brain. In the region of the brain that controls motor activity, the disease destroys critical dopamine-producing neurons. The loss of these neurons, along with the associated loss of dopamine, leads to muscle stiffness, slowed movements, and ultimately to the involuntary shaking that is the classic symptom of Parkinson’s. No cure for the disease is currently known.
Genetics are known to play an important role in the development of Parkinson’s. 17 regions of the human genome have been identified where frequent variations in sequencing appear to increase the risk of developing the disease. Researchers have also identified nine specific genes that can mutate into Parkinson’s disease.
In the study, neurons were derived from the skin cells of patients with various inherited forms of Parkinson’s disease. Mitochondrial deficits associated with Parkinson’s were observed in all samples, and cellular responses to treatments varied depending on the type of Parkinson’s affecting the donor patient.
The skin cells were first transformed into induced pluripotent stem cells. These cells, called iPS cells, are adult cells that have been reprogrammed to mimic embryonic stem cells. The cells were then manipulated into neurons using a combination of growth stimulating molecules and favorable conditions.
The study used iPS cells from patients with mutations in the leucine-rich repeat kinase-2 enzyme encoded by the PARK8 gene and from patients with mutations in the PTEN-induced putative kinase-1 serine / threonine protein Kinase derived from the PINK1 gene. Both mutations are known to cause Parkinson’s disease.
The researchers observed the oxygen consumption rates of the mitochondria in the derived cells. Mitochondria use oxygen to extract cellular energy from glucose. Parkinson’s disease has been linked to mitochondrial dysfunction.
The oxygen consumption rates were observed to be lower in cells derived from patients with LRRK2 mutations and higher in cells derived from patients with PINK1 mutations. The administration of the immunosuppressant rapamycin has been found to help prevent damage to LRRK2 mutated cells but not to neurons with PINK1 mutations.
These results suggest that Parkinson’s disease, which comes from different genetic causes, can benefit from different medical treatments. IPS cell technology could be used to identify subsets of patients in clinical trials. Parkinson’s intervention studies have never focused on specific genetic groups.