For more than 150 years, ALS has been recognized by experts as a motor neuron disease. But scientists still remain unsure why these cells are especially vulnerable to destruction in people with ALS or why they ultimately fail during the course of the disease.
An international group of neuroscientists led by University of Edinburgh’s Siddharthan Chandran MD PhD, King’s College London’s Christopher Shaw MBChB MD FRACP FRCP and Columbia University’sTom Maniatis PhD hopes to begin to answer these questions by recreating ALS-ravaged motor neurons in laboratory dishes and studying their neurodegeneration.
Now, the UK-US research team reports that they have hit their first milestone: the generation of a so-called induced pluripotent stem (iPS) cell line created from an ALS patient skin biopsy that can be used to cook up motor neurons in the laboratory. Incredibly, the motor neurons induced appear to be in working order – capable of firing electrical signals used to ‘tell’ muscles to move – and exhibit tell-tale signs of the disease.
This is the first time that researchers have been able to recreate apparently functional motor neurons in the laboratory from a person with ALS.
The study is published this month in the Proceedings of the National Academy of Sciences.
Not an exact match. Researchers discovered that induced ALS motor neurons accumulate misfolded TDP-43 (green). But unlike more than 90% of people with ALS, these aggregates do not build up in the cytoplasm. Image:Bilican, B et al. (2012). Courtesy of the National Academy of Sciences Press.
The UK-US research team created a ‘line’ of ALS iPS cells by turning back the cellular clocks of a patient’s skin cells and culturing them. The scientists then splashed these iPS cells with a few chemicals to push them into motor neuronal mode.
Peering under the microscope, the researchers found that the resulting motor neurons somewhat resembled those in people with ALS. The cells were nearly 3-times more prone to degeneration. And, misfolded proteins accumulated in them.
Meanwhile, neuroscientists at Nationwide Children’s Hospital in Ohio hope to up the ante by introducing key inflammation instigators such as microglia and astrocytes into the mix to truly recreate ALS in laboratory dishes. Just last September, the research team led by neuroscientist Brian Kaspar PhDreported the successful reconstitution, using spinal cord tissue from ALS patients, of a key aspect of astrocytosis – the astrocyte-mediated destruction of neighboring motor neurons – which in part fuels the progression of the disease.
Looking ahead, these cellular systems could help scientists uncover underlying mechanisms of ALS and at the same time, pave the way toward the development of personalized therapies to treat the disease.