Researchers from Nagoya University in Japan have identified a new genetic variant found in some patients with amyotrophic lateral sclerosis (ALS).
Using human induced pluripotent stem (iPS) cells, they detailed the process by which this variant relates to ALS. The researchers say they expect this mechanism to be a new therapeutic target for the treatment of ALS.
The results were reported in the Journal of Neuroscience.
ALS is a progressive and fatal neurodegenerative disease in which a person gradually loses motor neurons and develops muscle weakness. The mechanisms and causes of this disease are not well understood and there is no treatment. Moreover, ALS is a diverse disease; different patients seem to have different causes, mechanisms and symptoms.
Researchers know that a protein called fused sarcoma (FUS) plays a key role in the disease. Usually, FUS binds to RNA and regulates RNA functions. However, FUS dysfunctions are associated with various neurodegenerative diseases, including ALS.
Satoshi Yokoi and his colleagues from the Department of Neurology at Nagoya University Medical School studied this FUS protein. Previously, they found that the FUS protein interacted with RNA that codes for a protein called SYNGAP1. SYNGAP1 helps with synaptic formation, which is essential for neurons to work together.
“Currently, no studies have reported that SYNGAP1 is involved in the mechanism of ALS. However, given its close relationship with FUS, we wanted to determine if SYNGAP1 had anything to do with ALS,” Yokoi said, one of the main authors of the study.
First, the team looked for a variant of the SYNGAP1 gene in patients with ALS. They found seven of 807 patients who had the variant. Then, to examine the behavior of the SYNGAP1 variant, they replicated this variant gene in human motor neurons derived from iPS. An iPS cell is a type of stem cell that scientists can transform into any type of cell in the body, including neurons. It is particularly useful in medical research because researchers can generate, for example, diseased cells and perform different tests on them in a living state.
This contrasts with traditional methods in which researchers perform tests on animal cells or outside of a living organism. In this study, the researchers generated motor neurons with the SYNGAP1 variant from iPS cells. In these neurons, the researchers observed several abnormal behaviors compared to normal motor neurons.
In particular, the variant overrecruited the FUS protein, as well as another RNA-binding protein called HNRNPK. This excessive binding inhibited synaptic formation. In particular, over-recruitment of HNRNPK, rather than FUS, appeared to be a primary cause of synaptic dysfunction with the SYNGAP1 variant.
Developing drugs for ALS
When the researchers applied an antisense RNA that blocks HNRNPK from over-binding to SYNGAP1 RNA, they recovered synaptic formation, meaning motor neurons can function together. This indicates that in the future, scientists could use antisense RNA to develop drugs for ALS.
Excessive binding of HNRNPK to SYNGAP1 caused synaptic abnormality. This explains the ALS process at an early stage when synapse loss takes place. Additionally, while previous ALS research has focused on FUS, this study highlighted the crucial roles of SYNGAP1 and HNRNPK. The antisense RNA used in the current research is only effective for patients with the SYNGAP1 variant. Nevertheless, the researchers hope that the discovery of this new mechanism can provide new information on other types of ALS.
The study also revealed that SYNGAP1 behaved differently in human iPS cells compared to the mouse model, which had been used for SYNGAP1 research.
“We believe the use of human-derived samples is crucial for the observations of these cells to apply directly to patients,” Yokoi said.
Although researchers have described a mechanism for ALS, there is still much to study because ALS involves several different mechanisms and causes.
“The ALS patients I see in my daily practice have not yet received a cure. We will continue our research to find something that can be applied to future treatments for ALS,” concluded Yokoi.
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