Breaking News
July 16, 2018 - Advanced Prostate Cancer Variant More Common Than Thought
July 16, 2018 - New ways to conquer sleep apnea compete for place in bedroom
July 16, 2018 - Renowned microbe hunter Stanley Falkow dies at 84 | News Center
July 15, 2018 - FDA Slaps Stronger Warnings on Potent Class of Antibiotics, Fluoroquinolones
July 15, 2018 - Don’t let depression keep you from exercising
July 15, 2018 - Student research symposium showcases curiosity and scholarship | News Center
July 15, 2018 - Heavy smokers have increased risk of heart rhythm disorder, shows study
July 15, 2018 - Parents who had severe trauma, stresses in childhood more likely to have kids with behavioral health problems
July 15, 2018 - At colloquium, a range of views on value of predictive algorithms | News Center
July 15, 2018 - Pittcon invites oral and poster presentations for 2019 Technical Program
July 15, 2018 - Virtual reality could offer psychotherapy for fear of heights, study shows
July 15, 2018 - Retooled vaccine raises hopes as a lower-cost treatment for Type 1 diabetes
July 15, 2018 - Kolon TissueGene To Start US Phase III Clinical Trial For Invossa
July 15, 2018 - Study finds prenatal marijuana use can affect infant size, behavior
July 15, 2018 - Howard Chang named HHMI investigator | News Center
July 15, 2018 - Study shows tailored mental health services improve wellbeing of emerging adults
July 15, 2018 - A bright future might help teens steer clear of violence
July 15, 2018 - Stanford Medicine magazine explores the art, science of listening and hearing | News Center
July 15, 2018 - New study tracks how the brain turns simple sensory inputs into meaningful categories
July 15, 2018 - Deadlier subtype of metastatic prostate cancer found to be common than previously thought
July 15, 2018 - UZH scientists identify enzyme that controls cell division
July 15, 2018 - Unhealthy Food Behaviors May Signal Eating Disorder in Teen
July 15, 2018 - Study raises doubts on a previous theory of Parkinson’s disease
July 15, 2018 - Grant awarded to study whether stem cells can treat urinary incontinence | News Center
July 15, 2018 - Imaging techniques may help assess immune system recovery in HIV patients
July 15, 2018 - Machine-learning may aid in diagnosis and treatment of mental health disorders
July 15, 2018 - ‘Skin Cancer, Take A Hike!’ program promotes sun safety and skin cancer awareness
July 15, 2018 - Blink Health announces lowest prices for generic prescriptions through Blue Eagle Health
July 15, 2018 - New drug strategy can alleviate multiple behavioral, cellular deficiencies in FXS mouse model
July 15, 2018 - Georgia State professor receives federal grant to study virus similar to Ebola virus
July 15, 2018 - Quitting Smoking? Even a Little Exercise Can Help You Stay Slim
July 15, 2018 - DBS treatment may slow the progression of Parkinson’s tremor in early-stage patients
July 15, 2018 - 5 Questions: Luby on virus with potential to cause global pandemic | News Center
July 15, 2018 - Corn loses its cancer-fighting phenolic acids when processed into cornflakes
July 15, 2018 - Study uncovers possible link between iron loading, alcohol intake and mortality
July 15, 2018 - Molecular insights of NagA enzyme could help combat TB
July 15, 2018 - The Facts on Tampons—and How to Use Them Safely
July 15, 2018 - Normalisation of ‘plus-size’ risks hidden danger of obesity, study finds
July 15, 2018 - $2.5 million award to support physician-scientist training | News Center
July 15, 2018 - Aeras announces publication of Phase 2 results of two TB vaccines
July 15, 2018 - Public to set research priorities in field of ethnic inequalities and severe mental illness
July 15, 2018 - Eisai and Biogen Announce Positive Topline Results of the Final Analysis for BAN2401 at 18 Months
July 15, 2018 - U.S. obesity rates rising again
July 15, 2018 - Millions could have incorrect statin, aspirin and blood pressure prescriptions | News Center
July 15, 2018 - Researchers identify factors associated with cell phone-related distracted driving in parents
July 15, 2018 - Bioethicists suggest ethical considerations for forensic use of genetic data
July 15, 2018 - Most clinical trial participants find benefits of sharing personal data outweigh risks, Stanford study finds | News Center
July 14, 2018 - Researchers solve protein puzzle that paves way for new cancer therapies
July 14, 2018 - Blood telomeres can help predict risk of disease worsening or death in COPD patients
July 14, 2018 - CDC: Nearly One-Third of Injury Deaths Occur at Home
July 14, 2018 - Injectable electronics offer powerful new tool in understanding how retinal cells work
July 14, 2018 - Human blood cells transformed into functional neurons | News Center
July 14, 2018 - Podcast: KHN’s ‘What the Health?’ ACA under fire. Again.
July 14, 2018 - Small device with motion sensors can predict older adults’ risk of falling
July 14, 2018 - Neurological Fallout From Ebola Infection Worse Than Thought
July 14, 2018 - Screening for impaired vision in older adults: New Canadian guideline
July 14, 2018 - Blood test for pregnant women can predict premature birth, Stanford-led study reports | News Center
July 14, 2018 - Study uncovers process that neutralizes tumor cells
July 14, 2018 - Four-protein biomarker blood test improves lung cancer risk assessment for smokers
July 14, 2018 - Researchers develop novel approach to bridge gap in cell-free systems
July 14, 2018 - Research reveals new gears in the circadian clock
July 14, 2018 - Researchers assess role of physician in preventing intimate partner violence perpetration
July 14, 2018 - Two diabetes medications don’t slow progression of type 2 diabetes in youth
July 14, 2018 - New clues to restoring fertility in women with disabling ovary disorder
July 14, 2018 - Compound in citrus oil could reduce dry mouth in head, neck cancer patients | News Center
July 14, 2018 - Streck ARM-D Kits detect more antibiotic resistance than comparable tests
July 14, 2018 - Study finds wide variations in follow-up imaging for women with non-metastatic breast cancer
July 14, 2018 - FDA expands its support for states to implement FSMA Produce Safety Rule
July 14, 2018 - CTI BioPharma Announces the Continuation without Modification of PAC203 Phase 2 Study of Pacritinib in Patients with Myelofibrosis Previously Treated with Ruxolitinib
July 14, 2018 - First-hand accounts of premature baby loss inspires new resource
July 14, 2018 - Study identifies cellular ‘death code’ | News Center
July 14, 2018 - Federal judge enters consent decree against Minnesota dairy farm for selling adulterated meat
July 14, 2018 - New web-based game motivates people to exercise more
July 14, 2018 - Calcium electrotransfer could be used to target cancer cells, study finds
July 14, 2018 - Researchers identify new region in mouse brain that affects appetite and body weight
July 14, 2018 - Repeated testing produces ‘practice effect’ that obscures true cognitive decline
July 14, 2018 - Amgen And UCB Resubmit Biologics License Application (BLA) For Evenity (romosozumab) To The US FDA
July 14, 2018 - New research detects brain cell that improves learning
July 14, 2018 - Spirit, Inspiring Change award winners announced | News Center
July 14, 2018 - Opioid patients face several barriers to treatment, study finds
Scientists discover basic molecular mechanism that helps understand how ALS works

Scientists discover basic molecular mechanism that helps understand how ALS works

image_pdfDownload PDFimage_print

It took eight long years of research, but now an international team led by neuroscientists at Université de Montréal has discovered a basic molecular mechanism that better helps understand how Lou Gehrig’s disease, or amyotrophic lateral sclerosis (ALS), works.

And that basic science could someday lead to new therapy for the debilitating disease, which cripples people by removing the brain’s ability to communicate with their muscles, eventually leading to paralysis and early death.

“It’s a story of fundamental research about what happens normally in the body’s cells and what changes in the context of ALS,” said Jade-Emmanuelle Deshaies, a research associate in neurosciences at the UdeM Hospital Research Centre (CRCHUM) and lead author of the joint Canada-Israel study, published online today in the journal Brain.

“While studies such as this do not immediately give rise to new treatments for people living with ALS, they do deepen our understanding of the disease. ALS is very complicated; many cellular functions get mis-regulated. This type of work provides important information for future drug targets and the development of biomarkers aimed at detecting the disease more rapidly and following its progression.”

The research began eight years ago when Deshaies and her supervisor, associate professor of neurosciences Christine Vande Velde, started investigating what happens to various molecules when TDP-43, a protein that binds the ‘messengers’ in the cell known collectively as RNA and that is central to ALS pathology, is removed from the nucleus.

“Our specific focus was on other types of RNA binding proteins that could be interesting players in the disease,” Deshaies recalled. “One of these, hnRNP A1, caught our eye. In particular because there was a second form that is rarely mentioned in the literature.”

How the science works

But first, a bit of basic science.

In molecular biology, genes encode RNA and the RNA then gets translated into proteins, the workhorses of cells. There are many different versions of RNA, each encoding many different versions of a protein. TDP-43, for one, binds RNA and can change how it is spliced – in a sequence of ABCD, for example, or of ABCEFG – a process called alternative splicing. Another RNA binding protein is hnRNP A1, and it gets spliced into two variants, both regulated by TDP-43.

Why is this important to understanding ALS? Because TDP-43 is known to be a major component of non-living substances in the cell called cytoplasmic inclusions, which are observed in 97 per cent of ALS cases.

“The data we have show that when TDP-43 is either not there at all, or is just absent from the nucleus, you can change the splicing pattern of hnRNP A1,” said Vande Velde. “The big picture is that there is a much more broad spectrum of RNA metabolism mis-regulation than what was previously thought. And with that, we get more understanding of what’s going wrong, and given this new knowledge, we can potentially develop a therapy that targets this mechanism.”

Another motor neuron disease, SMA

A parallel development is research into another motor neuron disease, spinal muscular atrophy (SMA). Scientists know that hnRNP A1 plays a role in its progress, controlling the splicing of an important gene called SMN, survival motor neuron. Vande Velde and her team don’t yet know whether or not the new splice variant they discovered changes SMN levels or function, but they point to a new drug therapy announced last year for SMA that does target the splicing of SMN by hnRNP A1.

“The drug is nusinersen, sold commercially as Spinraza,” Vande Velde explained. “When you give it to babies early enough, you can fix their spinal muscular atrophy. Babies that were not able to roll over, or walk, now can. Babies that would normally die within the first two or three years of life are able to reach the developmental milestones. It’s being reported as a real cure for the most severe forms of the disease.”

Developed by scientists at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals, nusinersen is an exciting development “because they did the type of work we’ve been doing, which is to understand how a gene is spliced” said Vande Velde. That’s a therapeutic that came out of understanding a molecular mechanism involving alternative splicing.

“It took many years to get to that point, and similarly, our work is just the first cog in the wheel,” she added. “Whether or not there really is an influence on the expression or the splicing of the very important gene SMN, or other genes important for motor neuron survival, is something we need to evaluate,” Vande Velde said.

Persistence pays off

Her lab’s work is also a story of persistence. As Deshaies put it, “science is rarely straightforward. It often takes a winding road before leading to explanations and true understanding of what we observe.”

“We’re studying a mechanism that’s never been reported before,” Vande Velde noted. “We had some conflicting results early on, and it took time to figure out what the role of TDP-43 was in all this. It was “a massive team undertaking,” she added, “with team members from Israel (at Hebrew University), Quebec (at UdeM and Université de Sherbrooke) and elsewhere in Canada (at Western University) all making key contributions.”

More ALS research is done in Quebec than any other province, and the UdeM-led study was supported by grants from NSERC and the non-profit ALS Society of Canada. Hence the importance of getting the news out, even with no new therapy in sight.

“I think it’s an important service to communicate back to patients and their families what discoveries are being made with their donations, like those given via the Ice Bucket Challenge” said Vande Velde. “Many families are eager to learn about the molecular details of the disease and how we get to know them, and understand this is an important step in developing a therapy.”

Source:

http://nouvelles.umontreal.ca/en/article/2018/03/19/better-understanding-als-by-looking-at-how-cells-change/

Tagged with:

About author

Related Articles