Patient-derived Stem Cells Could Improve Drug Research for Parkinson's
Researchers have taken a step toward personalized medicine for Parkinson's disease, by investigating signs of the disease in patient-derived cells and testing how the cells respond to drug treatments. The study was funded by the National Institutes of Health.
The researchers collected skin cells from patients with genetically inherited forms of Parkinson’s and reprogrammed those cells into neurons. They found that neurons derived from individuals with distinct types of Parkinson's showed common signs of distress and vulnerability — in particular, abnormalities in the cellular energy factories known as mitochondria. At the same time, the cells' responses to different treatments depended on the type of Parkinson's each patient had.
A consortium of researchers conducted the study with primary funding from NINDS. The consortium is led by Ole Isacson, M.D., Ph.D., a professor of neurology at McLean Hospital and Harvard Medical School in Boston.
The NINDS consortium's first goal was to transform the patients' skin cells into induced pluripotent stem (iPS) cells, which are adult cells that have been reprogrammed to behave like embryonic stem cells. The consortium researchers then used a combination of growth conditions and growth-stimulating molecules to coax these iPS cells into becoming neurons, including the type that die in Parkinson's disease.
Parkinson's disease affects a number of brain regions, including a motor control area of the brain called the substantia nigra. There, it destroys neurons that produce the chemical dopamine. Loss of these neurons leads to involuntary shaking, slowed movements, muscle stiffness and other symptoms. Medications can help manage the symptoms, but there is no treatment to slow or stop the disease.
Most cases of Parkinson's are sporadic, meaning that the cause is unknown. However, genetics plays a strong role. There are 17 regions of the genome with common variations that affect the risk of developing Parkinson's disease. Researchers have also identified nine genes that, when mutated, can cause the disease.
Dr. Isacson and his collaborators derived iPS cells from five people with genetic forms of Parkinson's disease. By focusing on genetic cases, rather than sporadic cases, they hoped they would have a better chance of seeing patterns in the disease process and in treatment responses. Three of the individuals had mutations in a gene called LRRK2, and two others were siblings who had mutations in the gene PINK1. The researchers also derived iPS cells from two of the siblings' family members who did not have Parkinson's or any known mutations linked to it.
Because prior studies have suggested that Parkinson's disease involves a breakdown of mitochondrial function, the researchers looked for signs of impaired mitochondria in patient-derived neurons. Mitochondria turn oxygen and glucose into cellular energy. The researchers found that oxygen consumption rates were lower in patient cells with LRRK2 mutations, and higher in cells with the PINK1 mutation. In PINK1 mutant cells, the researchers also found increased vulnerability to oxidative stress, a damaging process that in theory can be counteracted with antioxidants.
Next, the researchers tested if neurons derived from patients and healthy volunteers were vulnerable to a variety of toxins, including some that target mitochondria. Compared to neurons from healthy individuals, patient-derived neurons were more likely to become damaged or die after exposure to mitochondrial toxins. Patient-derived neurons also suffered more damage from the toxins than did patient-derived skin cells.
The NINDS Parkinson's Disease iPS Cell Research Consortium is one of three such consortia funded by NINDS. One of the consortia is focused on developing iPS cells for the study of Huntington's disease, and another focuses on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
Skin cell and iPS cell lines developed by the consortia are available to both academic and industry researchers through the NINDS human cell line repository at the Coriell Institute. To date the NINDS repository has distributed more than 200 cell lines worldwide.