Stem cells are the body's master cells. They have the ability to differentiate and grow into any one of the body's more than 200 cell types. Stem cells can renew and repair its tissues by replacing dying cells or to restore tissue after injury.
Induced pluripotent stem cells are derived from adult cells; at The Parkinson’s Institute we use adult skin cells. Skin cells are then turned or reprogrammed into stem cells that mimic an embryonic stem cell state. This new technique called ‘nuclear reprogramming’ is very powerful and can coax any cell into stem cell-like cells by forced expression of a known set of proteins. These iPS cells are almost indistinguishable from human embryonic stem cells, but are derived from an adult, which leaves the heated ethical discussion about stem cells behind.
iPS cells provide a major advance towards the development of “authentic” Parkinson’s disease in a Petri Dish, in which Parkinson’s disease-specific cellular and molecular changes can be studied. iPS cells derived from patients with Parkinson’s disease lay the foundation for further differentiation into the tissue type of interest for PD, the midbrain dopaminergic neuron. The iPS cells also give rise to other cell types of interest and provide a method of creating cells with a patient specific genetic make-up.
To model Parkinson's disease in a Petri Dish we transform patient iPS cells into dopaminergic neurons, which is considered the closest representation of the brain outside the human body.
The goal of this study is to develop iPS cells from patients who have defined mutations and sporadic forms of Parkinson’s disease. These cell lines will be used as an experimental pre-clinical model to study disease mechanisms unique to PD. We predict that these cells will not only serve as an “authentic” model for PD when further differentiated into dopaminergic neurons, but that these cells are actually pathologically “affected with PD”.
Parkinson’s in a Petri Dish is believed to greatly advance three main areas:
A pluripotent stem cell can become any type of cell in the body. A multipotent stem cell has already become one type of family of cells, such as one from a neuronal lineage. This multipotent cell can then become any type of brain cell, but is no longer able to become a heart muscle cell or skin cell.
Neural stem cells are the self-renewing, multipotent cells that can generate the main cell types of the brain: neurons and glia cells.
We make these neural stem cells from skin-derived iPS cells. They can be propagated and we use them as a source to differentiate, or transform, them into mature dopaminergic neurons.
Dopaminergic neurons are nerve cells in the midbrain which synthesize and contain the neurotransmitter dopamine. Midbrain dopaminergic neurons are positioned within three cell groups in the brainstem including the substantia nigra. In Parkinson’s disease, dopaminergic neurons in the substantia nigra die or degenerate which can cause the motor symptoms of Parkinson’s disease.
Mitochondria are the cell's power plants. They convert energy substrates into special energy forms used by the cell.
Mitochondrial dysfunction has been frequently implicated in the neurodegenerative process that underlies Parkinson’s disease, and the basis for this impairment is not fully understood. Considering the essential role of mitochondria in cellular energy metabolism, calcium buffering, cellular quality control and cell death regulation, mitochondrial dysfunction can probably be considered a major risk factor contributing to high vulnerability of midbrain dopaminergic neurons in PD patients.
Zinc-finger technology is a novel technique to repair genetic mutations. This molecular tool acts like a ‘scissor’ in the cell and can cut the DNA in the nucleus at defined positions, so that genetic mutations can be edited and ‘repaired’.
With this approach we will be able to investigate the effects of specific mutations in iPS cell lines that are only different by the disease-causing mutation, thus representing a ‘genetically virtually identical’ control cell line.
The ability to correct genetic defects would be a major milestone in the treatment of human disease. We focus on a specific genetic form of PD, LRRK2 G2019S, as a proof-of-principle combined with iPS technology. The ability to study the activity of either the normal or the mutant gene product in cells derived from one individual could be a critical tool for elucidating the function of disease-related genes and mutations. These cellular models could become important tools for drug screening approaches.