Induced pluripotent stem cells (iPSCs) are made from adult cells by means of genetic engineering techniques that introduce specific genes into the adult cell and force it to de-differentiate into an embryonic-like cell. This procedure might provide cells for therapeutic uses some day, but this technology must overcome the mutations introduced into these cells by this procedure and the tumors they can cause. Until then, iPSCs will remain off-limits as therapeutic tools.
That does not disqualify iPSCs as tools for research and even therapeutic investigation. This present paper that comes from a collaborative effort led by Ole Isacson, professor of neurology at McLean Hospital and Harvard Medical School in Boston, uses this very strategy to examine the response of patients with particular forms of Parkinson’s disease to various drugs.
Parkinson’s disease is a progressive, insidious disease that affects a portion of the brain called the midbrain. Within the midbrain is a black body called the substantia nigra, which is Latin for “black stuff.” The substantia nigra is rich in neurons that release a neurotransmitter called “dopamine.”
First of all, to review, neurotransmitters are chemicals that neurons (the cells that make and transmit nerve impulses to other neurons in the brain) use to talk to each other. Neurotransmitters bind to the surfaces of nearby neurons and initiate the production of a nerve impulse. If the neuron receives enough neurotransmitter, it will generate a nerve impulse. Neurons typically can only respond to particular neurotransmitters. The neurotransmitters to which they respond elicit particular responses from them.
Parkinson’s disease results from the death of dopamine-releasing neurons in the midbrain. These neurons connect to cells of the “striatum.” The striatum is responsible for balance, movement control, and walking. Dopamine, produced in the substantia nigra, passes messages between the striatum and the substantia nigra, and when the cells of the substantia nigra deteriorate, which is the case of Parkinson’s disease, there is a corresponding decrease in the amount of dopamine produced between these cells. The decreased levels of dopamine cause the neurons of the striatum to fire uncontrollably, and this prevents the patient from properly controlling their direct motor functions.
Most of the cases of Parkinson’s disease are spontaneous and have no apparent cause. However, there are several types of inherited forms of Parkinson’s and mutations in approximately 17 different genes are associated with inherited forms of Parkinson’s disease. Of these, only nine have been studied in any detail. Nevertheless, two genes in particular are important in this paper.
Isacson found two Parkinson’s patients with inherited forms of the disease. One of then had a mutation in the LRRK2 (Leucine-rich repeat kinase-2) gene, which encodes the Dardarin protein and is intimately involved in the onset of Parkinson’s disease. The other had a mutation in the PINK1 gene (PTEN induced putative kinase 1), which encodes a protein known to enter mitochondria (the powerhouses of the cell). Isacson used cells from each patient to make iPSCs. He also used additional patients, and he had a total of 3 patients with mutations in LRRK2 and two with mutations in PINK1.
Because mutations in LRRK2 and PINK1 are thought to interfere with the function of mitochondria in neurons, Isacson examined the mitochondria of these patient-specific iPSCs. When compared to mitochondria from volunteers without Parkinson’s disease, Isacson found that the Parkinson’s patient-specific iPSCs were much more susceptible to damage after exposure to toxins. Thus, the mitochondria of these patient-specific iPSCs were certainly much more fragile than normal mitochondria.
Could this mitochondrial fragility be ameliorated with medicines? Isacson tested the ability of particular substance to mitigate this condition in the patient-specific iPSCs. A supplement called Q10, which is known to aid mitochondrial function was administered the to Parkinson’s patient-specific iPSCs, was given to the cells, and all cells were prevented from experiencing mitochondrial damage after exposure to toxins. However, when a different drug called rapamycin was administered, the results were very different. Rapamycin diminishes the immune response of an organism, and therefore, it can spare weak cells from being cleared by the immune system. Rapamycin prevented damage in the cells with mutations in LRRK2, but not those with mutations in PINK1.
This paper shows how iPSC-based research can lead to information that can fashion personal treatments for each patient. Even though this work focused on Parkinson’s disease, there are many other diseases that could benefit from iPSC-based research.