By Ashley Juavinett
We typically think of disease as a systemic problem – for example, a person with amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) gradually loses the ability to move, indicating an underlying issue with motor systems. More recently, we have begun to consider diseases in a genetic light, noting that diseases often have corresponding genetic abnormalities such as mutations in SOD1, C9ORF72, TDP-43, or FUS.
Now, with the nascent ability to model diseases in a dish using cultured human neurons, we can also begin to examine diseases in terms of their cell-specific effects: what happens to a particular type of neuron when its host organism is affected by a debilitating disease such as ALS?
Back in 2006, a group from Japan showed that you could take human skin cells and “de-differentiate” them; in other words, turn them back into stem cells, wiping the slate blank for their function (Takahashi & Yamanaka, 2006). You can then take these induced pluripotent stem (iPS) cells as they are now known, and program them into neurons by allowing them to grow in a dish in the presence of certain growth factors. Although these cells started life differently, they have the same genome as regular neurons, giving us a unique look at the downstream cellular effects of certain genes.
Fred Gage and colleagues have already had success with modeling schizophrenia in this way. By comparing neurons from schizophrenic patients and healthy controls, they discovered that the schizophrenic neurons had less synapses with different genetic markers, and that the antipsychotic loxapine reversed these abnormalities (Brennand et al., 2011). The hope is that similar types of observations could be made with motor neuron diseases such as ALS, to potentially move us closer to better treatments for this presently incurable disease (Winner et al., 2014).
To study ALS, scientists transformed iPS cells into a particular type of cell involved in helping us do almost everything related to voluntary as well as involuntary movement: a motor neuron. ALS is marked by progressive loss of these neurons in the cortex, brainstem, and spinal cord, ultimately causing the patient to completely lose the ability to move. Motor neurons that are derived from patients with ALS have the same genetic make-up from their host patient, allowing scientists to study particular genes associated with the disorder (Gage, 2010).
In 2011, a group of scientists in La Jolla, California did just the above. They focused on an autosomal dominant form of familial ALS called ALS8, affecting about 10% of people with ALS. First mapped in a Brazilian family, and later in patients with German and Japanese ancestry, ALS8 is caused by a mutation in the VAPB gene. Using iPSCs from ALS8 patients and their non-carrier siblings, they showed that there was indeed a decrease in VAPB proteins in ALS8-derived neurons, supporting previous observations from the sporadic form of ALS (Mitne-Neto et al., 2011).
Just this past March, an international team of scientists published a study about iPS cells derived from an ALS patient with a specific TDP-43 mutation known as M337V. TDP-43 is a DNA/RNA binding protein that is normally found in the nucleus, but has an abnormal pathology in diseases such as ALS and frontotemporal lobar degeneration. Consistent with previous observations, the researchers found that the patient’s cells had increased cytosolic levels of TDP-43. In addition to this proof-of-concept for using iPS cells, they found something quite groundbreaking: they could transfect these cells with an allele-specific small-interference RNA (siRNA) to effectively reduce levels of TDP-43 (Nishimura et al., 2014). This provides some preliminary evidence that RNA interference may be useful for developing ALS therapeutics.
Of course, studying diseases in a dish cannot tell us everything we need to know, and is still several steps away from bedside therapies. But as iPS cell technology continues to improve and integrate with other technologies such as RNA interference, there are many avenues of research that may ultimately prove very beneficial to developing treatments for ALS as well as other motor neuron disorders. In the words of Tom Insel, NIMH director, “From astronomy to microbiology, new technology has often been the portal to new understanding.”
Guest Blogger Profile
Ashley Juavinett is a UCSD neurosciences PhD student, an NSF Graduate Research Fellow, and an aspiring science writer. Working at the Salk Institute (La Jolla, CA), Ashley is using in vivo imaging to investigate the neural circuitry underlying visual perception in mice. She currently co-directs a collaborative science writing group, NeuWrite San Diego (http://www.neuwriteSD.org), and writes about neuroscience and society on her own blog (http://scramblingforsignificance.blogspot.com). Follow her on Twitter: @ashleyjthinks