HNRNPK

Researchers have identified a variant of the gene in some patients with amyotrophic lateral sclerosis (ALS). Using human-induced pluripotent stem (iPS) cells, subsequent investigations revealed this variant excessively recruited RNA-binding proteins and disrupted the synaptic formation, which is considered the early impairment in ALS. When excessive binding was blocked, synaptic formation was recovered. These findings describe one of the mechanisms that cause ALS and offer new insights for treatment. Researchers at Nagoya University in Japan have identified a novel genetic variant found in some patients with Amyotrophic lateral sclerosis (ALS). Employing human-induced pluripotent stem (iPS) cells, they detailed the process by which this variant relates to ALS. The investigators expect this mechanism to be a new therapeutic target for ALS treatment. The findings are reported in the Journal of Neuroscience. ALS is a progressive and fatal neurodegenerative disease where a person gradually loses motor neurons and has muscle weakness. The mechanisms and causes of this disease are not well understood and there is no treatment. Furthermore, ALS is a diverse disease; different patients seem to have different causes, mechanisms, and symptoms. Researchers know that a protein called Fused-in sarcoma (FUS) plays a key role in the disease. Ordinarily, FUS binds to RNA and regulates functions of RNA. On the other hand, FUS dysfunctions are associated with various neurodegenerative diseases, including ALS. Dr. Satoshi Yokoi and his colleagues in the Department of Neurology, Nagoya University Graduate School of Medicine, have been studying this FUS protein. Previously, they found that the FUS protein interacted with RNA that encodes a protein called SYNGAP1. SYNGAP1 helps with synaptic formation, which is essential for neurons to work together. "Currently, no study has reported that SYNGAP1 is involved in the mechanism of ALS. However, given its close relationship with FUS, we wanted to investigate whether SYNGAP1 has anything to do with ALS," said Dr. Yokoi, a lead author of the study. First, the team searched for a variant of the SYNGAP1 gene in patients with ALS. They found seven out of 807 patients who had the variant. Next, to examine the behavior of the SYNGAP1 variant, they replicated this variant gene in human iPS-derived motor neurons. 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 especially useful in medical research because researchers can generate, for example, diseased cells and conduct different tests on them in a living state. This contrasts with traditional methods in which researchers conduct 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, researchers observed several abnormal behaviors compared to normal motor neurons. Especially, the variant excessively recruited the FUS protein, as well as to another RNA-binding protein called HNRNPK. This excessive binding inhibited synaptic formation. In particular, excessive recruitment of HNRNPK, rather than FUS, seemed to be a primary cause of synaptic dysfunction with the SYNGAP1 variant. Furthermore, when researchers applied antisense RNA that blocks the excessive binding of HNRNPK to SYNGAP1 RNA, they recovered synaptic formation, meaning that motor neurons can work together. This indicates that, in the future, sscientists could utilize antisense RNA to develop ALS drugs. Excessive binding of HNRNPK to SYNGAP1 was causing synaptic abnormality, which explains the process of early-stage ALS when synapse loss takes place. Additionally, while previous ALS research focused on FUS, this study underscored the crucial roles of SYNGAP1 and HNRNPK. The antisense RNA used in the current research is only effective for those patients with the variant SYNGAP1. Nonetheless, the researchers hope that the discovery of this new mechanism can provide new insight into other types of ALS. Interestingly, this study also found that SYNGAP1 behaved differently in human iPS cells compared to the mouse model, which had been used for SYNGAP1 research. "We believe that using human-derived samples is crucial so that the observations from these cells directly apply to patients," said Dr. Yokoi. Although the researchers described one mechanism of ALS, much remains to be investigated because ALS involves multiple different mechanisms and causes. "The ALS patients I see in my daily practice have yet to receive curative treatment. We will continue research to find something that can apply to future ALS treatments," said Dr. Yokoi.

Researchers have identified a previously unknown mechanism controlling tumor growth in cultured cells and mice. This discovery may potentially enable future development of new drugs against a range of cancer diseases. Researchers at the University of Gothenburg have identified a previously unknown mechanism controlling tumor growth in cultured cells and mice. This discovery may potentially enable future development of new drugs against a range of cancer diseases. In a research article published in the journal Nature Communications, the Gothenburg scientists have described their discovery. It concerns a protein that binds genetic material and, as the researchers now show, also controls properties that regulate tumor development. The protein -- known as HnRNPK -- binds to messenger-RNA (mRNA), which the two genes IER3 and IER3-AS1 code for. These genes are highly active in several forms of cancer. By binding to the mRNA of these genes, the HnRNPK prevents double-strand RNA forming between them and keeps them separate. Changes in tumor growth "Keeping these two genes' RNA separate promotes growth of tumors that depend on growth factors. Without the HnRNPK protein, the properties that promote tumor growth are neutralized, paving the way for development of drugs that block the HnRNPK," says Chandrasekhar Kanduri, Professor of Medical Genetics at Sahlgrenska Academy, University of Gothenburg, who is one of the research leaders behind the study. The study also shows that, similarly, the HnRNPK protein binds to the mRNA of several other genes, preventing the formation of double-strand RNA. The discovery affords scope for indirectly influencing the FGF-2 growth factor, which is well known to be key both to the process whereby stem cells mature into various cell types and to early embryonic development. Fewer side effects Meena Kanduri, Associate Professor (Docent) of Molecular Medicine at Sahlgrenska Academy, is the corresponding author of the article. "Given the crucial role of FGF-2 in normal human development, using drugs that target the growth factor directly would have too many side effects. The mechanism we've now identified is part of the same signaling chain, but further downstream. So, the mechanism has the potential to become a more attractive cancer treatment option, with fewer side effects," she says. More research is needed to verify the transferability of the finding from cell culture and mouse studies to humans. In the next stage, the group plans to conduct extended studies to examine in more detail how the pair of genes regulated by FGF-2 govern the growth environment of tumors.