Nav: Home

CRISPR helps find new genetic suspects behind ALS/FTD

March 12, 2018

NIH-funded researchers at Stanford University used the gene editing tool CRISPR-Cas9 to rapidly identify genes in the human genome that might modify the severity of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) caused by mutations in a gene called C9orf72. The results of the search, published in Nature Genetics, uncovered a new set of genes that may hasten neuron death during the disease.

Accounting for nearly 40 percent of inherited cases of ALS and 25 percent of inherited FTD cases, disease-causing mutations in C9orf72 insert extra sequences of DNA, called hexanucleotide repeats, into the gene. These repeats produce potentially toxic RNA and protein molecules that kill neurons resulting in problems with movement and eventually paralysis for ALS patients and language and decision-making problems for FTD patients.

Led by Aaron D. Gitler, Ph.D., and Michael C. Bassik, Ph.D., the researchers used CRISPR to disable each gene, one-by-one, in a line of human leukemia cells and then tested whether the cells would survive exposure to toxic proteins derived from the hexanucleotide repeats, called DPRs. Any disabled genes that caused cells to live longer or die faster than normal were considered suspects in DPR toxicity. They confirmed that genes that control the movement of molecules in and out of a cell's nucleus may be partners. They also identified several new players, including genes that modify chromosomes and that help cells assemble proteins passing through a maze-like structure called the endoplasmic reticulum (ER). A second CRISPR search conducted on mouse brain cells confirmed the initial results. Disabling the top 200 genes identified in the leukemia cells helped neurons survive DPR exposure.

Finally, further experiments highlighted the importance of the ER genes, especially one called TMX2. For instance, the researchers could cause neurons derived from the skin cells of ALS patients with C9orf72 to live longer than normal when they silenced the TMX2 gene, suggesting it could be exploited in designing novel therapies for ALS. Decreasing TMX2 in cells caused an increase in the production of "survival proteins" that the authors hypothesized protected the cells against DPR toxicity.

Previously such studies needed a few months to find candidate genes and could only be performed on yeast, worm, and fly genomes. With CRISPR, the researchers in this study needed just about two weeks to conduct a complete search of the human genome. The results suggest that this faster and more comprehensive approach may be used to rapidly identify genes that may be involved in other neurological disorders.

Kramer et al. CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9orf72 dipeptide repeat protein toxicity, March 5, 2018, Nature Genetics; DOI: 10.1038/s41588-018-0070-7

This study was supported by the NIH (NS097263, NS097850, NS069375, HD084069); the National Human Genome Research Institute Training Grant; the National Science Foundation Graduate Research Fellowship; the Department of Defense (W81XWH-15-1-0187); the Robert Packard Center for ALS Research at Johns Hopkins; Target ALS; the Stanford Brain Rejuvenation Project of the Stanford Neurosciences Institute; the Muscular Dystrophy Association; and the New York Stem Cell Foundation.

For more information:

NINDS is the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD conducts and supports research in the United States and throughout the world on fetal, infant and child development; maternal, child and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit NICHD's website.

NHGRI is one of the 27 institutes and centers at the National Institutes of Health. The NHGRI Extramural Research Program supports grants for research, and training and career development at sites nationwide. Additional information about NHGRI can be found at

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

NIH/National Institute of Neurological Disorders and Stroke

Related Human Genome Articles:

Science and legal experts debate future uses and impact of human genome editing in Gender & the Genome
Precise, economical genome editing tools such as CRISPR have made it possible to make targeted changes in genes, which could be applied to human embryos to correct mutations, prevent disease, or alter traits.
Evolution purged many Neanderthal genes from human genome
Neanderthal genetic material is found in only small amounts in the genomes of modern humans because, after interbreeding, natural selection removed large numbers of weakly deleterious Neanderthal gene variants, according to a study by Ivan Juric and colleagues at the University of California, Davis, published Nov.
Mathematical analysis reveals architecture of the human genome
Mathematical analysis has led researchers in Japan to a formula that can describe the movement of DNA inside living human cells.
Navigating the human genome with Sequins
Australian genomics researchers have announced the development of Sequins -- synthetic 'mirror' DNA sequences that reflect the human genome.
Scientists cut 'Gordian knot' in the human genome
Females have two X chromosomes in each of their cells.
Guidelines for human genome editing
As countries around the world seek to craft policy frameworks governing the powerful new genetic editing tool, policy makers need to determine 'thresholds of acceptability' for using the technology, according to three researchers from the Centre of Genomics and Policy at McGill University.
Predicting the human genome using evolution
By observing evolution's 'greatest hits' (and misses) and the history of the major themes and patterns of genome conservation (and divergence) across many species, Temple University professor Sudhir Kumar's approach predicts probable mutations that will be found among people and the fate of human variation.
JAX reseachers, collaborators report on variations in human genome
A consortium of international researchers, including Charles Lee, Ph.D., of The Jackson Laboratory for Genomic Medicine, have reported findings from a massive research project exploring variations in the human genome, including structural variations.
Scientists discover new system for human genome editing
A team including the scientist who first harnessed the revolutionary CRISPR-Cas9 system for mammalian genome editing has now identified a different CRISPR system with the potential for even simpler and more precise genome engineering.
The human genome: A complex orchestra
A team of Swiss geneticists from the University of Geneva, the École Polytechnique Fédérale de Lausanne, and the University of Lausanne discovered that genetic variation has the potential to affect the state of the genome at many, seemingly separated, positions and thus modulate gene activity, much like a conductor directing the performers of a musical ensemble to play in harmony.

Related Human Genome Reading:

Genome: The Autobiography of a Species in 23 Chapters
by Matt Ridley (Author)

The genome's been mapped.
But what does it mean?

Arguably the most significant scientific discovery of the new century, the mapping of the twenty-three pairs of chromosomes that make up the human genome raises almost as many questions as it answers. Questions that will profoundly impact the way we think about disease, about longevity, and about free will. Questions that will affect the rest of your life.

Genome offers extraordinary insight into the ramifications of this incredible breakthrough. By picking one newly discovered gene from each pair of chromosomes and... View Details

The Human Genome: " The Complete Nucleic Acid Sequence for Human DNA "
by Edited by Paul F. Kisak (Author)

The human genome is the complete set of nucleic acid sequence for humans (Homo sapiens), encoded as DNA within the 23chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. Human genomes include both protein-coding DNA genes and noncoding DNA. Haploid human genomes, which are contained in germ cells (the egg and spermgamete cells created in the meiosis phase of sexual reproduction before fertilization creates a zygote) consist of three billion DNAbase pairs, while diploid genomes (found in somatic cells) have twice the DNA content. While there are... View Details

The Human Genome, Third Edition
by Julia E. Richards (Author), R. Scott Hawley (Author)

Significant advances in our knowledge of genetics were made during the twentieth century but in the most recent decades, genetic research has dramatically increased its impact throughout society. Genetic issues are now playing a large role in health and public policy, and new knowledge in this field will continue to have significant implications for individuals and society. Written for the non-majors human genetics course, Human Genetics, 3E will increase the genetics knowledge of students who are learning about human genetics for the first time. This thorough revision of the best-selling... View Details

The Mysterious World of the Human Genome
by Frank Ryan (Author)

The human genome is indeed a mysterious world, but, as this fascinating book shows, its vital secrets are now being uncovered. The latest studies are revealing exciting new discoveries, such as how the DNA and related chemical compounds in our cells work together to direct the processes of life. Scientists are not only unraveling how life evolved in the ancient past, but are also finding the keys to creating a healthier future.  

How does the minuscule chemical cluster in each of our 100 trillion cells accomplish the amazing feat of creating and maintaining our bodies? Frank Ryan, a... View Details

The Deeper Genome: Why there is more to the human genome than meets the eye
by John Parrington (Author)

Over a decade ago, as the Human Genome Project completed its mapping of the entire human genome, hopes ran high that we would rapidly be able to use our knowledge of human genes to tackle many inherited diseases, and understand what makes us unique among animals. But things didn't turn out that way. For a start, we turned out to have far fewer genes than originally thought -- just over 20,000, the same sort of number as a fruit fly or worm. What's more, the proportion of DNA consisting of genes coding for proteins was a mere 2%. So, was the rest of the genome accumulated 'junk'?... View Details

The Common Thread: A Story of Science, Politics, Ethics and the Human Genome
by Georgina Ferry (Author), John Sulston (Author)

The world was agog when scientists made the astounding announcement that they had successfully sequenced the human genome. Few contributed so directly to this feat as John Sulston. This is his personal account of one of the largest international scientific operations ever undertaken.

It was a momentous occasion when British scientist John Sulston embarked on the greatest scientific endeavor of our times: the sequencing of the Human Genome. In The Common Thread, Sulston takes us behind the scenes for an in-depth look at the controversial story behind the headlines. The... View Details

Ancestors in Our Genome: The New Science of Human Evolution
by Eugene E. Harris (Author)

In 2001, scientists were finally able to determine the full human genome sequence, and with the discovery began a genomic voyage back in time. Since then, we have sequenced the full genomes of a number of mankind's primate relatives at a remarkable rate. The genomes of the common chimpanzee (2005) and bonobo (2012), orangutan (2011), gorilla (2012), and macaque monkey (2007) have already been identified, and the determination of other primate genomes is well underway. Researchers are beginning to unravel our full genomic history, comparing it with closely related species to answer age-old... View Details

The Human Genome: Book of Essential Knowledge (Curiosity Guides)
by John Quackenbush (Author), John Sulston (Foreword)

The DNA sequence that comprises the human genome--the genetic blueprint found in each of our cells--is undoubtedly the greatest code ever to be broken. Completed at the dawn of a new millennium, the feat electrified both the scientific community and the general public with its tantalizing promise of new and better treatments for countless diseases, including Alzheimer's, cancer, diabetes, and Parkinson's. Yet what is arguably the most important discovery of our time has also opened a Pandora's box of questions about who we are as humans and how the unique information stored in our genomes can... View Details

The Human Genome Diversity Project: An Ethnography of Scientific Practice (Cambridge Studies in Society and the Life Sciences)
by Amade M'Charek (Author)

The Human Genome Diversity Project was an important controversial research program arising from the debates surrounding the mapping of the human genome. This book, based on a detailed ethnographic study of two laboratories involved in the project, explores issues concerning standardization, naturalization and diversity generated in day-to-day work by scientists and technicians. View Details

Modern Prometheus: Editing the Human Genome with Crispr-Cas9
by James Kozubek (Author)

Would you change your genes if you could? As we confront the 'industrial revolution of the genome', the recent discoveries of Crispr-Cas9 technologies are offering, for the first time, cheap and effective methods for editing the human genome. This opens up startling new opportunities as well as significant ethical uncertainty. Tracing events across a fifty-year period, from the first gene splicing techniques to the present day, this is the story of gene editing - the science, the impact and the potential. Kozubek weaves together the fascinating stories of many of the scientists involved in... View Details

Best Science Podcasts 2018

We have hand picked the best science podcasts for 2018. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

The Consequences Of Racism
What does it mean to be judged before you walk through the door? What are the consequences? This week, TED speakers delve into the ways racism impacts our lives, from education, to health, to safety. Guests include poet and writer Clint Smith, writer and activist Miriam Zoila Pérez, educator Dena Simmons, and former prosecutor Adam Foss.
Now Playing: Science for the People

#465 How The Nose Knows
We've all got a nose but how does it work? Why do we like some smells and not others, and why can we all agree that some smells are good and some smells are bad, while others are dependant on personal or cultural preferences? We speak with Asifa Majid, Professor of Language, Communication and Cultural Cognition at Radboud University, about the intersection of culture, language, and smell. And we level up on our olfactory neuroscience with University of Pennsylvania Professor Jay Gottfried.