The study led by Dr. Stephen J. Kolb
of the Department of Neurology at Ohio State’s Wexner Medical Center and Dr. Brian K. Kaspar
of The Research Institute at Nationwide Children’s Hospital, is published in PNAS
Direct conversion is a recently established method to generate neuronal progenitor cells (NPCs) from skin fibroblasts in a fast and efficient manner. In this study, researchers show that direct conversion can be used to model neurodegenerative diseases such as ALS. Because the origin of ALS is mainly sporadic with unknown cause, methods to model the disease are urgently needed.
The produced NPCs are differentiated into astrocytes, which are involved in motor neuron death in ALS. Skin-derived astrocytes show similar toxicity toward motor neurons as astrocytes from autopsies of patients. This tool now allows studying ALS while the patient is still alive and can help in testing potential therapeutics for individual patients.
“Trying to model ALS is very difficult because we don’t know what causes it, and most of our models for neurodegenerative diseases are based on genetic models,” said Kolb, who is also a member of the Department of Molecular and Cellular Biochemistry at Ohio State and the Center for RNA Biology at Ohio State’s Wexner Medical Center. “In neurodegenerative diseases, it is difficult to study the cells that are involved while the individual with the disease is still alive.”
“This study opens the door to a rapid and efficient manner in which to model an ALS patient. Within a month we can take a skin fibroblast from a patient and direct those cells into motor neurons, astrocytes and oligodendrocytes, all cells involved in this disease,” said Kaspar, who is also a member of the Department of Neuroscience at Ohio State. “Once we have generated patient specific cells, we can start to investigate why motor neurons are dying, in our attempts to understand the underlying mechanisms for what is going wrong in this devastating disease.”
The study was funded by U.S. National Institutes of Health Grants R01 NS644912-4 and RC2 NS69476-01, a Packard Center for ALS Research Grant P2ALS and the Helping Link Foundation to Dr. Kaspar’s research program.
“This is a prime example of clinical and basic scientists working together to create personalized model systems to model each patient’s individual disease,” said Kaspar. “We are trying to determine what makes astrocytes toxic to motor neurons in patients who develop ALS, and how to block that toxicity.”
May is ALS Awareness Month, designed to bring attention to this devastating disorder affecting mainly upper and lower motor neurons in the motor cortex, brainstem and spinal cord. Patients typically suffer from muscular atrophy and paralysis, ultimately leading to death within 5 years after diagnosis. Approximately 5,600 people in the United States are diagnosed with ALS each year, and it is estimated that as many as 30,000 Americans may have the disease at any given time, according to the ALS Association
Other researchers include Kathrin Meyer, Laura Ferraiuolo, Carlos J. Miranda, Shibi Likhite, Sohyun McElroy, Samantha Renusch, Dara Ditsworth, Clotilde Lagier-Tourenne, Richard A. Smith, John Ravits, Arthur H. Burghes, Pamela J. Shaw and Don W. Cleveland.