Researchers have discovered a new way by which a gene mutation can kill neurons in people with ALS and a related disease, frontotemporal dementia, or FTD.

Their discovery, published in the journal Neuron, could offer researchers a new approach to treating these incurable conditions.

The gene mutation leads to the production of a faulty version of the TIA1 protein. The normal version facilitates what researchers call phase separation a process that allows cell components to assemble into membrane-less structures crucial to normal cell function.

When the protein malfunctions, the structures fail to disassemble, causing proteins to accumulate in nerve cells. This ultimately kills the neurons, researchers from St. Jude Childrens Research Hospital and Mayo Clinic said. They published their findings in an article titledTIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Their studyprovides a link to earlier observations that another protein, TDP-43, is often found in protein aggregates inALS patients.The researchers discovered that when TDP-43 was trapped in such protein assemblies, it became more insoluble.

This paper provides the first smoking gun, showing that the disease-causing mutation changes the phase transition behavior of proteins, Dr. J. Paul Taylor, chair of St. Judes Cell and Molecular Biology Department, said in a press release.

And the change in the phase transition behavior changes the biology of the cell, added Taylor, who led the study along with Dr. Rosa Rademakers of the Mayo Clinic operation in Jacksonville, Florida.

The path to discovering the importance of phase separation in amyotrophic lateral sclerosis started with a family that had ALS and FTD. The family had a mutated TIA1 protein. But when researchers discovered it some time back, they did not know what the implications of the mutation could be.

The studies, which included an analyses of the mutated proteins properties, led to the discovery that TIA1 mutations are common in people with ALS. When analyzing brains of deceased ALS patients who carried abnormal TIA1 genes, researchers found aggregates of what scientists call stress granules.

These TIA1-containing structures form when a cell is exposed to stressful conditions such as heat, chemical exposure, and aging.

The teams experiments revealed that TIA1 mutations made the protein stickier. This prevented the stress granules from breaking up and trapped TDP-43 in the process.

These findings are part of an emerging theme that there is a whole spectrum of diseases that includes ALS, and some forms of dementia and myopathy, that are caused by disturbance in the behavior of these structures that perturbs cellular organization, said Taylor, who said the results offer the first approach to treating ALS effectively.

Current therapies, which can slow the diseases progression only slightly, work by trying to improve the function of damaged neurons. In contrast, restoring phase separation may actually prevent nerve cell damage.

We know that these material properties are under tight regulation, so perhaps we dont have to target the disease-causing mutation itself, Taylor said. Perhaps we can restore balance by targeting any of a large number of regulatory molecules in the cell. There are already therapeutic approaches in laboratory testing that seek to do just that.

The team is now working on achieving a better understanding of phase transition properties. Their ultimate goal is to find ways to restore the processes, which may also be involved in other neurodegenerative conditions, including Alzheimers disease.

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ALS Mutation Kills Nerve Cells by Preventing Protein Clumps from Breaking Apart, Study Reports - ALS News Today

Philip Howe Ph.D., the senior author on the Nature Cell Biology article, is chair of the Department of Biochemistry & Molecular Biology at the Medical University of South Carolina (MUSC) and the Hans and Helen Koebig Endowed Chair in Oncology at the MUSC Hollings Cancer Center Credit: Medical University of South Carolina

A mechanism that pushes a certain gene to produce a non-coding form of RNA instead of its protein-coding alternative can promote the growth of cancer, report researchers at the Medical University of South Carolina (MUSC) in an article published online ahead of print on August 21, 2017 by Nature Cell Biology. The non-coding RNA soaks up a microRNA that prevents epithelial-to-mesenchymal transition, one of the key features of tumor development.

From one gene, cells can often produce different forms of RNA. The exact pre-RNA copy of one strand of DNA in a gene must be cut and assembled into its final RNA form, or several forms, in a process known as alternative splicing. Yet while these alternative forms of RNA can encode different proteins, scientists are discovering that many types of RNA do not, instead performing vastly different functions that regulate cell fate and behavior. MicroRNAs, for example, home in on certain protein-coding RNAs and help degrade them.

It is another class, called long non-coding RNAs (lncRNA), that are of particular interest to Philip H. Howe, Ph.D., chair of the Department of Biochemistry & Molecular Biology, and the Hans and Helen Koebig Endowed Chair in Oncology at the MUSC Hollings Cancer Center. Howe and his team found that a pre-RNA for a protein called PNUTS can be alternatively spliced to form a lncRNA that contributes to cancer progression. The PNUTS lncRNA does not encode a protein, but rather soaks up like a sponge a certain microRNA that is usually tasked with preventing epithelial-to-mesenchymal transition, which is a key feature of tumor growth and metastasis.

Howe's group connected a number of dots to explain how this happens. First, they found that breast cancer cells contained more PNUTS lncRNA than normal breast epithelial cellsa good initial sign that the non-coding RNA was associated with cancer development. Those cells were also more mesenchymal, meaning that they were more likely to form tumors.

They next examined a ribonucleoprotein called hnRNP E1, which binds to pre-RNA and suppresses alternative splicing. Importantly, they knew that TGF-beta, which is released in large amounts by tumor cells, could prevent its binding, potentially allowing alternate forms to be made. Computer models predicted that this ribonucleoprotein could bind to PNUTS pre-RNA on its alternative splicing site. In lung and breast cancer cell lines, specially designed RNA probes confirmed that this exact splicing site was more exposed when the ribonucleoprotein was knocked down and that those cells had more PNUTS lncRNA. When cells were exposed to TGF-beta over time, PNUTS lncRNA was made in increasing amounts. It turns out that the ribonucleoprotein was bound more tightly with the alternative splice site. In normal conditions, this allowed PNUTS protein to be made, but in tumors, the alternative splice site became exposed and more lncRNA was made instead.

Yet the group wanted to confirm exactly how PNUTS lncRNA could encourage tumor formation. Additional computer simulations predicted that, based on its sequence, there were seven potential locations on the PNUTS lncRNA for microRNA-205 to bind. This microRNA binds and destroys a transcriptional regulator called ZEB1 that encourages cells to unstick from one another and spreada major step that allows epithelial-to-mesenchymal transition to occur. As predicted, without those potential binding locations, the lncRNA and the microRNA were unable to bind together. This helped cells stick together and spread less, even with TGF-beta added to push them to spread.

It appeared that PNUTS lncRNA was soaking up microRNA-205, which freed up ZEB1 to encourage cells to act more like tumors. To be sure that this was true, the group stuck fluorescent molecules to ZEB1 to track it and found that more of it was present when there were more PNUTS lncRNA.

As expected, preclinical models revealed that breast and lung tumors grew faster and larger when their cells contained more PNUTS lncRNA. By connecting all of the dots, Howe's group had shown that one gene can make either a protein-coding RNA or a long non-coding RNA. With TGF-beta, the lncRNA soaked up microRNA-205 like a sponge, freeing up ZEB to drive epithelial-to-mesenchymal transition, a critical event in the development and spread of cancer.

This is the first study to show exactly how TGF-beta drives cancer through formation of a long non-coding RNA. Howe and his team are conducting experiments to find other such long non-coding RNAs that follow this same mechanism in cancer, with the goal of developing therapies to target them.

"My prediction is that this mechanism didn't evolve to make just one long non-coding RNA," says Howe. "There are probably others that are generated in this same fashion."

Explore further: Long non-coding RNA modulates colorectal cancer metabolism

More information: A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression, Nature Cell Biology (2017). DOI: 10.1038/ncb3595

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How a non-coding RNA encourages cancer growth and metastasis - Medical Xpress

A gift from alumnus Paul Heidger 63, along with a matching grant from the Colorado Department of Higher Education, to provide $113,000 investment in UNCs honors program.

Heidger, a graduate of the universitys inaugural honors class, recently established the Barbara Heidger Opportunity Scholarship Endowment in honor of his late wife. The two met as honor students at UNC, then Colorado State College, when the institution created the honors program in 1959.

I sincerely hope this scholarship bearing Barbaras name, together with knowledge of her life story and accomplishments in education, in promotion of global awareness and peace, and in self-giving service to others may assist similarly inspired young women and men at UNC to reach their life goals and full potential, Paul said.

Heidger and his family established the fund to honor Barbaras legacy and her passion for international students. Earnings will be used to support current and incoming honors students, with a preference for those interested in international relations and education. Heidger plans to establish an additional honors program scholarship for students interested in science.

The generous giftfrom Paul and his family will provide supportfor years to come.These scholarships help UNC to recruit the best and brightest into our Honors Program, which seeks to develop tomorrow's problem solvers, said UNC Director for Honors and Scholars Loree Crow. Scholarship support of these motivatedstudents is essential to building the strongest cohorts and is invaluable to the individual students who often need just a little extra to help them succeed at their highest potential.

Paul Heidger 63 and Barbara (Hyslop) Heidger 63 first met as members of the inaugural Honors class, and the bonds and memories formed between them, their classmates and professors have lasted a lifetime.

At Paul and Barbaras wedding, fellow honors classmate, Bill Hayes, served as best man and classmate Sharon Wilson (now a UNC Professor Emerita) was one of Barbaras attendants. Dr. Eugene Koplitz, UNC professor and first honors program director, and honors Professor Dr. Forrest Frease and their families were honored guests.

Paul and Barbara were dedicated to their passions Pauls in biology and Barbaras in international affairs and both achieved accomplished paths of service to their professions. Barbaras untimely passing in 1994 at the height of her personal and professional life impacted family, students, colleagues and friends around the world. She was a devoted wife and mother to their daughters, Julie and Lisa, and a passionate educator and ambassador for international understanding. Paul recently retired from the University of Iowa, where he was a professor of Anatomy and Cell Biology.

Pauls initial gift of $60,000 created the endowment and, through a Colorado Opportunity Scholarship Initiative (COSI) grant from the Colorado Department of Higher Education, much of Pauls gift will be matched, bringing the total impact on the Honors Program to approximately $113,000. The Honors Program plans to use these funds to create scholarships for exceptional incoming freshmen and to attract more top honors students to UNC.

The Campaign for UNC goal is $45 million, and every dollar and every donor counts. Donors from across our community are contributing to the mission and success of UNC students, faculty and programs. Every gift matters. Gifts of all amounts are moving the mark and letting UNC's new generation know that Bears take care of Bears.

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First UNC Honors Alum Gives Back to Future Educators - UNCO News Central