Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

3-D Changes in DNA May Lead to a Genetic Form of Lou Gehrig’s Disease

Published: Friday, March 07, 2014
Last Updated: Friday, March 07, 2014
Bookmark and Share
NIH-funded scientists reveal how a genetic code variation results in devastating brain diseases.

New findings reveal how a mutation, a change in the genetic code that causes neurodegeneration, alters the shape of DNA, making cells more vulnerable to stress and more likely to die.

The particular mutation, in the C9orf72 gene, is the most common cause for amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), and frontotemporal degeneration (FTD), the second most common type of dementia in people under 65.

This research by Jiou Wang, Ph.D., and his colleagues at Johns Hopkins University (JHU) was published in Nature and was partially funded by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS).

In ALS, the muscle-activating neurons in the spinal cord die, eventually causing paralysis. In FTD neurons in particular brain areas die leading to progressive loss of cognitive abilities. The mutation may also be associated with Alzheimer’s and Huntington’s diseases.

DNA contains a person’s genetic code, which is made up of a unique string of bases, chemicals represented by letters. Portions of this code are divided into genes that provide instructions for making molecules (proteins) that control how cells function.

The normal C9orf72 gene contains a section of repeating letters; in most people, this sequence is repeated two to 25 times. In contrast, the mutation associated with ALS and FTD can result in up to tens of thousands of repeats of this section.

Using sophisticated molecular techniques, Dr. Wang and his team showed that the mutation causes changes in the three-dimensional shape of DNA. DNA is normally shaped like a twisted ladder. However, the repeating sequences can fold into G-quadruplexes, stacks of square-shaped molecules known as G-quartets. "This structure has been described as a square building with each floor representing one G-quartet, normally two to four stories high,” said Dr. Wang, senior author of the paper.

Their results also showed that C9orf72 mutated DNA has profound effects on how the genetic message is processed in the cell. RNA, short for ribonucleic acid, acts as an important intermediary - a middleman - in the process that converts genetic information from DNA into functional proteins. This happens in two stages: conversion of the DNA code into RNA is called transcription. RNA then forms proteins during a process known as translation.

The investigators discovered that the mutated DNA forms DNA-RNA hybrid structures called R loops. Then they showed that G-quadruplexes and R-loops interfered with the transcription process. Cells taken from patients (containing the C9orf72 mutation) produced shorter transcription products (or transcripts) compared with control cells (without the mutation) taken from healthy volunteers.

These short transcripts result in abnormal functioning of the cell and can lead to cell death. “Unfortunately, these alternative DNA arrangements impede normal processing, much like a car encountering a series of speed bumps or the occasional roadblock while traveling to its destination,” said Dr. Wang.

Findings from Dr. Wang’s team also suggest that the C9orf72 mutation has an effect in the nucleolus, a cellular structure located within the nucleus (which contains the cell’s DNA) and the site where initial steps in protein assembly occur. The nucleolus also plays a key role in directing the cell’s response to stress.

The key protein inside the nucleolus is nucleolin. Dr. Wang teamed with Jeffrey D. Rothstein, M.D., from JHU, to study the effects of the C9orf72 mutation on nucleolin. They found that binding of the short transcription products formed by the C9orf72 mutation to nucleolin has toxic effects on cells.

The researchers show that in healthy cells without the mutation, nucleolin is present only in a certain area of the nucleus, but in cells obtained from ALS patients, nucleolin is scattered throughout the nucleus. They postulate that abnormal distribution of nucleolin causes cells to become stressed and more likely to die, which can result in the pathology associated with ALS and FTD.

For those experiments, the researchers used induced pluripotent stem cells (iPSC) containing the C9orf72 mutation that were derived from the skin of ALS patients. The iPSCs can be turned into different types of cells, in this case into motor neurons, which are the cells that die in patients with ALS. The iPSC technology lets scientists study in a dish the direct effects of disease-causing human mutations on brain or spinal cord cells.

“Our new study, along with previous work, highlight the great power of ALS iPSCs,” said Dr. Wang.

Dr. Rothstein is the director of the ALS iPSC Consortium, which is managed by NINDS. The consortium is a resource that was created in 2009 to develop iPSCs for the study of genetic forms of ALS. The iPSCs are stored at the NINDS Human Genetics Repository and are available for use by researchers.

“The availability of iPSCs from patients and healthy volunteers enabled Dr. Wang and his collaborators to address directly the consequences of the C9orf72 mutation in human motor neurons, the brain cells responsible for movement,” said Margaret Sutherland, Ph.D., program director at NINDS.

“The findings described in Dr. Wang’s paper open up a new pathogenic mechanism for ALS and FTD by providing insight into the biology associated with the C9orf72 mutation and identifying a potential path forward for therapy development,” said Dr. Sutherland. For example, the alternative DNA structures (G-quadruplexes and R-loops) may be targets for potential drugs.

“Understanding the biology of C9orf72 is fundamentally important as we work with pharmaceutical companies to develop therapies for these highly devastating diseases,” said co-author Dr. Rothstein.

Further research is needed to provide a complete understanding of how the C9orf72 mutation leads to disease.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,500+ scientific posters on ePosters
  • More Than 5,000+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

“Sixth Sense” More Than a Feeling
NIH study of rare genetic disorder reveals importance of touch and body awareness.
Monday, September 26, 2016
“Sixth Sense” May Be More Than Just A Feeling
The NIH Study shows that two young patients with a mutation in the PIEZ02 have problems with touch and proprioception, or body awareness.
Friday, September 23, 2016
The Genetics of Blood Pressure
Researchers have identifed areas of the genome associated with blood-pressure including 17 previously unknown loci.
Wednesday, September 21, 2016
NIH Study Finds Link Between Depression, Gestational Diabetes
Researchers at NIH have discovered that the depression in early pregnancy doubles risk for gestational diabetes, and gestational diabetes increases risk for postpartum depression.
Tuesday, September 20, 2016
Detecting Bacterial Infections in Newborns
Researchers tested an alternative way to diagnose bacterial infections in infants—by analyzing RNA biosignatures from a small blood sample.
Wednesday, September 14, 2016
Finding Compounds That Inhibit Zika
Researchers identified compounds that inhibit the Zika virus and reduce its ability to kill brain cells.
Wednesday, September 14, 2016
Seeking Innovation to Combat Antimicrobial Resistance
Federal prize competition, with $20 million in prizes, seeks to develop new laboratory diagnostic tools to detect and distinguish antibiotic resistant bacteria.
Friday, September 09, 2016
Genetic Misdiagnoses of Heart Condition
Analysis found several genetic variations previously linked with a heart condition were harmless, leading to condition misdiagnosis.
Wednesday, September 07, 2016
Catalogue of Human Genetic Diversity Expands
The largest data set of human exomes to date has been assembled to better study seqence variants and their consequences.
Wednesday, September 07, 2016
Extreme Temperatures Could Increase Preterm Birth Risk
Researchers at NIH have found more preterm births among women exposed to extremes of hot and cold.
Friday, September 02, 2016
$12.4M Awarded to Neural Regeneration Projects
The National Institutes of Health will fund six projects to identify biological factors that influence neural regeneration.
Friday, September 02, 2016
Oxygen Can Impair Cancer Immunotherapy
Researchers have identified a mechanism within the lungs where anticancer immune resposnse is inhibited.
Friday, August 26, 2016
Diagnosing Bacterial Infections in Blood Samples
Researchers have diagnosed a bacterial infection from a blood sample in infants.
Wednesday, August 24, 2016
Stem Cell Therapy Heals Injured Mouse Brain
A team of researchers has developed a therapeutic technique that dramatically increases the production of nerve cells in mice with stroke-induced brain damage.
Tuesday, August 23, 2016
New Inflammatory Disease Discovered
NIH researchers have discovered a rare and potentially deadly disease - otulipenia - the mostly affects children.
Tuesday, August 23, 2016
Scientific News
Mass Spec Technology Drives Innovation Across the Biopharma Workflow
With greater resolving power, analytical speed, and accuracy, new mass spectrometry technology and techniques are infiltrating the biopharmaceuticals workflow.
One Step Closer to Precision Medicine for Chronic Lung Disease Sufferers
A study led by University of North Carolina at Chapel Hill, and National Jewish Health, has provided evidence of links between SNPs and known COPD blood protein biomarkers.
Gene Regulation in Brain May Explain Repetitive Behaviors in Rett Syndrome Patients
The research could be a key step in developing treatments to eliminate symptoms that drastically impair the quality of life in Rett patients.
Heart Arrhythmia Caused by Mosaic of Mutant Cells
Researchers have solved the genetic mystery of an infant suffering from heart arrhythmia.
Iron Nanoparticles Make Immune Cells Attack Cancer
Researchers accidentally discover that nanoparticles invented for anemia treatment can trigger the immune system’s ability to destroy tumor cells.
Crispr Toolbox Expanded By Protein
Researchers have shown a newly discovered CRISPR protein has two distinct RNA cutting activities.
CES Score May Predict Response to Cancer Treatment
Researchers identify new type of biomarker that helps predict prognosis and response to several types of cancer treatment.
Uncovering Cancer’s ‘Invisibility Cloak’
Researchers discover cancer cell mechanism to become invisible to the body's immune system.
Genetic Impact of Endurance Training
Research has found that endurance training changes genetic activity in thousands of genes, giving rise to large number of altered RNA variants.
Treating Sepsis with Marine Mitochondria
Mitochondrial alternative oxidase from a marine animal combats bacterial sepsis.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,000+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!