Nav: Home

Why nerve cells die in ALS and frontotemporal dementia

February 05, 2018

Scientists have for the first time discovered a mechanism that limits the number of "cellular janitors" in the nervous system, leading to increased risk for two neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, according to a Keck School of Medicine of USC study published today in Nature Medicine.

In the study, Yingxiao "TK" Shi and Shaoyu Sebastian Lin in the Justin Ichida Laboratory at USC Stem Cell describe how a mutation in a gene called C9ORF72 leads to toxicity in nerve cells. It causes 10 percent of all cases of ALS and an additional 10 percent of frontotemporal dementia.

"We figured out how the most common form of ALS causes nerve cell death, and nerve cell death is what causes patients to become paralyzed or lose control of neuromuscular functions," said Ichida, an assistant professor of stem cell and regenerative medicine at the Keck School of Medicine and a New York Stem Cell Foundation-Robertson Investigator.

Damage begins as a cellular chain reaction. Normally, the C9ORF72 gene, or C9, produces a protein that is required to make lysosomes, which act as cellular janitors to capture and remove toxic proteins and garbage. Without a normal amount of lysosomes, motor nerve cells accumulate toxic garbage and die.

To understand how this happens, the researchers extracted blood from ALS patients carrying the C9 mutation and reprogrammed these blood cells into motor nerve cells that degenerate and die in the disease. They also extracted blood from healthy patients, reprogrammed these blood cells into motor nerve cells and used gene editing to delete the C9 gene.

Whether patient-derived or gene-edited, all motor nerve cells with the mutation had reduced amounts of the protein normally made by the C9 gene. And by adding the supplemental C9 protein, the researchers could stop the motor nerve cells from degenerating.

"The C9 protein is required to construct the janitors of the cells, which are the lysosomes, and without them you have buildup of proteins in the cell that become a kind of toxic agent that causes the cells to die," Ichida said.

Specifically, insufficient lysosomes cause cells to accumulate two key types of garbage: a big, toxic protein produced by the mutated C9 gene and molecules that receive signals from a neurotransmitter known as glutamate. Too much glutamate hyperstimulates motor nerve cells to death, a phenomenon known as "excitotoxicity."

Guided by these discoveries, the Ichida Lab is now using the patient-derived motor nerve cells to test thousands of potential drugs, with focus on those that affect lysosomes. The goal is to find potential drugs that slow or stop degeneration of these motor nerve cells in petri dishes - and eventually in patients.

According to the National Institutes of Health, ALS is a group of rare neurological diseases that mainly involve the nerve cells (neurons) responsible for controlling voluntary muscle movement, such as chewing, walking and talking. ALS, sometimes called, Lou Gehrig's disease, is progressive and incurable at this time. It is part of a wider group of disorders known as motor neuron diseases. The U.S. Centers for Disease Control and Prevention estimates between 14,000 to 15,000 Americans have ALS.
-end-
Co-authors include Kim A. Staats, Yichen Li, Wen-Hsuan Chang, Shu-Ting Hung, Eric Hendricks, Gabriel Linares, Yaoming Wang, Brent Wilkinson, Louise Menendez, Toru Sugawara, Phillip Woolwine, Mickey Huang, Michael J. Cowan, Brandon Ge, Nicole Koutsodendris, K. Perry Sandor, Jacob Komberg, Valerie Hennes, Marcelo Coba and Berislav Z. Zlokovic from USC; Esther Y. Son from Stanford University; Xinmei Wen and Davide Trotti from Thomas Jefferson University; Kassandra Kisler and Amy R. Nelson from USC and Thomas Jefferson University; Vamshidhar R. Vangoor, Ketharini Senthilkumar, Leonard H. van den Berg, and R. Jeroen Pasterkamp from the University Medical Center Utrecht in the Netherlands; Tze-Yuan Cheng and Shih-Jong J. Lee from DRVision Technologies; Paul August from Icagen Corp.; Jason A. Chen, Nicholas Wisniewski, Victor Hanson-Smith, T. Grant Belgard and Alice Zhang from Verge Genomics; and Chris Grunseich and Michael Ward from the National Institute of Neurological Disorders and Stroke.

Seventy-five percent of the research was supported with federal funding totaling $6 million from the National Institutes of Health (AG039452, AG023084, NS034467, R00NS077435 and R01NS097850, T32DC009975-04) and the U.S. Department of Defense (W81XWH-15-1-0187). Twenty-five percent of the work was supported by $2 million from private and non-U.S. sources, including the ALS Foundation Netherlands (TOTALS), Epilepsiefonds (12-08, and 15-05), VICI grant Netherlands Organisation for Scientific Research (NWO), the Donald E. and Delia B. Baxter Foundation, the Tau Consortium, the Frick Foundation for ALS Research, the Muscular Dystrophy Association, the New York Stem Cell Foundation, the Regenerative Medicine Initiative at the Keck School of Medicine of USC, the USC Broad Innovation Award, the Southern California Clinical and Translational Science Institute, and the Walter V. and Idun Berry Postdoctoral Fellowship.

University of Southern California

Related Stem Cell Articles:

Interferon-beta producing stem cell-derived immune cell therapy on liver cancer
Induced pluripotent stem (iPS) cell-derived myeloid cells (iPS-ML) that produce the anti-tumor protein interferon-beta (IFN-beta) have been produced and analyzed by researchers from Kumamoto University, Japan.
Scientists aim to create the world's largest sickle cell disease stem cell library
Scientists at the Center for Regenerative Medicine at Boston Medical Center and Boston University School of Medicine are creating an induced pluripotent stem cell (iPSC)-based research library that opens the door to invaluable sickle cell disease research and novel therapy development.
Designer switches of cell fate could streamline stem cell biology
Researchers at the University of Wisconsin-Madison have developed a novel strategy to reprogram cells from one type to another in a more efficient and less biased manner than previous methods.
Allen Institute for cell science releases gene edited human stem cell lines
The Allen Institute for Cell Science has released the Allen Cell Collection: the first publicly available collection of gene edited, fluorescently tagged human induced pluripotent stem cells that target key cellular structures with unprecedented clarity.
Feng Zhang receives 2016 New York Stem Cell Foundation -- Robertson Stem Cell Prize
The New York Stem Cell Foundation (NYSCF) announced today that Feng Zhang, Ph.D., is the 2016 recipient of the NYSCF -- Robertson Stem Cell Prize for his pioneering advances to edit human and plant genomes using CRISPR-Cas9.
Scientists take aging cardiac stem cells out of semiretirement to improve stem cell therapy
With age, the chromosomes of our cardiac stem cells compress as they move into a state of safe, semiretirement.
Stem cell scientists discover genetic switch to increase supply of stem cells from cord blood
International stem cell scientists, co-led in Canada by Dr. John Dick and in the Netherlands by Dr.
More of a good thing is not always better -- and certainly not if you are a stem cell
Stem cell research led by the Babraham Institute has uncovered key new knowledge about how placental stem cells switch between maintaining a stem cell identity to setting off down the route to becoming specialized cell types.
A snapshot of stem cell expression
Research from the Wellcome Genome Campus demonstrates the power of single-cell genomics: Study reveals new genes involved in pluripotency, new subpopulations of cells and new methods to find meaning in the data.

Related Stem Cell Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Climate Crisis
There's no greater threat to humanity than climate change. What can we do to stop the worst consequences? This hour, TED speakers explore how we can save our planet and whether we can do it in time. Guests include climate activist Greta Thunberg, chemical engineer Jennifer Wilcox, research scientist Sean Davis, food innovator Bruce Friedrich, and psychologist Per Espen Stoknes.
Now Playing: Science for the People

#527 Honey I CRISPR'd the Kids
This week we're coming to you from Awesome Con in Washington, D.C. There, host Bethany Brookshire led a panel of three amazing guests to talk about the promise and perils of CRISPR, and what happens now that CRISPR babies have (maybe?) been born. Featuring science writer Tina Saey, molecular biologist Anne Simon, and bioethicist Alan Regenberg. A Nobel Prize winner argues banning CRISPR babies won’t work Geneticists push for a 5-year global ban on gene-edited babies A CRISPR spin-off causes unintended typos in DNA News of the first gene-edited babies ignited a firestorm The researcher who created CRISPR twins defends...