By Katie Moisse
Buried deep within our bony skulls and spinal columns, and separated from our blood by an infallible barrier, our neurons are, I would argue, the most protected cells in our bodies. This is a good thing for obvious reasons. This is a bad thing, however, for scientists studying neurodegeneration.
When induced pluripotent stem cells hit the scene four years ago, neuroscientists hoped for a lucky break: perhaps reprogramming fibroblasts from patients with Parkinson’s, Huntington’s and ALS into iPS cells and differentiating them into neurons genetically identical (almost) to the very cells that die off in their hosts would shed light on the cellular events unraveling in the depths of the central nervous system. Even better, maybe those sick, cultured neurons could be used to rapidly screen drugs aimed at slowing or even stopping the process.
But efforts to model diseases in culture using patient-derived iPS cells have generated mixed results. In some cases, the neurons harbour characteristics linked to their demise in vivo; whereas in others, the cells persist without incident despite expressing some of the deadliest disease-causing mutations.
Two years ago, researchers led by Harvard’s Kevin Eggan successfully generated iPS cells from an 82-year-old woman with familial (genetic) ALS and differentiated them into motor neurons—the subset of neurons selectively targeted causing progressive paralysis and death. The report, published in Science, was exciting 1) because aged fibroblasts could be reprogrammed at all and 2) because, for the first time, scientists could look at human motor neurons genetically destined to develop ALS under a microscope. But, so far, the cells appear to be disappointingly normal.
In contrast, when University of Wisconsin-Madison researchers led by Clive Svendsen (who I’ve blogged about before) concurrently derived iPS cells from a child with spinal muscular atrophy—a group of neuromuscular diseases similar to ALS but with earlier onset caused by mutations or deletions in the gene encoding SMN protein—the cells died at a higher frequency than iPS cell-derived neurons from the patient’s unaffected mother. Even better, the patient-derived iPS cells expressed protein aggregates considered to be a pathological hallmark that correlates with disease severity. Better still, drugs that promoted SMN protein expression in those patient-derived iPS cells reversed the pathology, demonstrating for the first time the potential for iPS cells in drug discovery. This work was published in Nature.
Could the neurodegenerative disease’s age of onset and genetic complexity influence its modelabilty? IPS cells from patients with Parkinson’s disease, Huntington’s disease and Down’s syndrome (which has characteristics of Alzheimer’s disease) lack any remarkable phenotype, according to a recent review published in Human Molecular Genetics. According to authors Maria Marchetto, Beate Winner and Fred Gage from La Jolla’s Salk Institute, “modeling late-onset neurodegenerative diseases and multifactorial neurodevelopmental diseases will require additional advances.”
So don’t discount iPS cells in neurodegenerative disease modeling yet, for their potential is “limited only by human creativity and ethical guidelines,” Marchetto and colleagues urge. “Neuroscientists in the past could not have imagined a scenario in which patient-derived neural cell types would be readily accessible to thousands of laboratories around the world, and researchers in the future will never imagine neuroscience without it.”