RESEARCH led by stem cell scientists at Harvard University points to a potential new biomarker and drug target for amyotrophic lateral sclerosis (ALS), a hard-to-diagnose and uniformly fatal neurologic disease. Published in Nature Neuroscience, the study used stem cell models of human motor neurons to reveal the gene STMN2 as a potential therapeutic target, demonstrating the value of this approach in drug discovery.
Patients with ALS (aka Lou Gehrig's Disease) experience the loss of motor neurons and progressive paralysis. Following a long diagnostic journey, most people do not survive longer than five years after the onset of symptoms. Two ALS drugs have been approved by the Food and Drug Administration, but they only act to slow the disease.
In addition to a cure--or even a treatment that is effective for more ALS patients--a robust test for ALS sorely is needed. For that to occur, scientists have to find a reliable biomarker of the disease.
About 10 years ago, scientists found aggregates of a protein called TDP-43 in postmortem neurons from ALS patients. This protein should have been in the nucleus of those neurons, but instead it was being flushed out, and building up in the cytoplasm. Clearly, some of the genes at work in the trash-disposal system of neurons, known as the proteasome, were interacting with TDP-43 in a way that precipitated ALS, but which genes are involved and what they are doing had not been known.
The gene that encodes for TDP-43 can be mutated to trigger ALS. It is passed on to future generations, who then develop either ALS or, in some cases, frontotemporal dementia (FTD), a group of disorders stemming from the progressive loss of neurons in the brain's frontal and temporal lobes. Since TDP-43 aggregates were discovered in ALS patients, they have been well known as a hallmark of the disease.
TDP-43 is one of many proteins that binds to RNA, which is responsible for transmitting genetic information and translating it into a concise recipe for a given protein, for example, part of a growing neuron. The researchers set out to identify, for the first time, all the possible types of RNA regulated by the TDP-43 protein in the context of human neurons. Until now, studies like this have been carried out only in mice and cancer cell lines.
The scientists subsequently looked at what happened to each gene when they manipulated TDP-43. The researchers reduced the levels of TDP-43 protein in human stem cell-derived motor...