Breaking News
October 21, 2018 - Income and wealth affect the mental health of Australians, study shows
October 21, 2018 - Patients with hypertension and psoriasis more often require cardiovascular interventions
October 20, 2018 - Leading hip-hop videos depict use of tobacco and marijuana products, study finds
October 20, 2018 - Dose Range of IV Ketamine for Adjunct Tx of Depression Tested
October 20, 2018 - Infants can distinguish between leaders and bullies, study finds
October 20, 2018 - Mad Cow disease found on Aberdeenshire farm
October 20, 2018 - Study identifies factors associated with prescription opioid misuse among students
October 20, 2018 - Scientists uncover key regulator of mTORC1 in cancer growth
October 20, 2018 - Pounds Regained After Weight-Loss Op Can Tell Your Doc a Lot
October 20, 2018 - Sending parents letters to fight childhood obesity doesn’t work
October 20, 2018 - Supervised aerobic exercise can support major depression treatment
October 20, 2018 - Mindfulness-based program effective for reducing stress in infertile women
October 20, 2018 - Molecule capable of halting and reverting neurodegeneration caused by Parkinson’s disease identified
October 20, 2018 - Midazolam-mediated alterations of PER2 expression may have functional consequences during myocardial ischemia
October 20, 2018 - Sweat bees are ideal for studying the genes underlying social behavior
October 20, 2018 - Weight loss success associated with brain areas involved in self-control
October 20, 2018 - KHN’s ‘What the Health?’ Republicans’ preexisting political problem
October 20, 2018 - Research provides a more complete picture of suffering caused by terrorist attacks
October 20, 2018 - Eradicating Helicobacter pylori infections may be a key treatment for Parkinson’s disease
October 20, 2018 - Breast Cancer as a Dynamic Disease
October 20, 2018 - University of Pittsburgh wins NSF grant for big data research to prevent complications from anesthesia
October 20, 2018 - Skin-to-skin contact may promote attachment between parents and preterm infants
October 20, 2018 - Recommendations Developed to Verify NGT Placement in Children
October 20, 2018 - Weight loss can be boosted fivefold thanks to novel mental imagery technique
October 20, 2018 - Children with autism are more likely to be overweight, obese
October 20, 2018 - Nurses making conscientious objections to ethically-relevant policies lack support
October 20, 2018 - Prion strain diversity may be greater than previously thought
October 20, 2018 - Antidepressant treatment may lead to improvements in sleep quality of patients with depression
October 20, 2018 - Study reports increased risk of death in children with inflammatory bowel disease
October 20, 2018 - Number of Autism Genes Now Tops 100
October 20, 2018 - Total diet replacement programmes are effective for treating obesity
October 20, 2018 - CLARIOstar used for fluorescence measurements on CSIRO’s purpose-built research vessel
October 20, 2018 - People with more copies of AMY1 gene digest starchy carbohydrates faster
October 20, 2018 - Case Comprehensive Cancer Center wins NIH grant to study health disparities
October 20, 2018 - Newly discovered compound shows potential for treating Parkinson’s disease
October 20, 2018 - High rate of non-adherence to hormonal therapy found among premenopausal early breast cancer patients
October 20, 2018 - Immunotherapy medicine found to be effective in treating uveitis
October 20, 2018 - The Pistoia Alliance Calls for Greater Collaboration to Realise Benefits of Innovation and Announces Winners of the 2018 President’s Startup Challenge
October 20, 2018 - Female internists consistently earn less than men
October 20, 2018 - Stanford team looks at dangers of teens’ vaping habits
October 20, 2018 - New approach to understanding cancers will accelerate development of better treatments
October 20, 2018 - LJI and UC San Diego awarded $ 4.5 million as part of NCI’s Cancer Moonshot initiative
October 20, 2018 - School-based HPV vaccination did not increase risky sexual behaviors among adolescent girls
October 20, 2018 - Eye discovery to pave way for more successful corneal transplants
October 20, 2018 - New analysis examines the importance of location in the opioid crisis
October 20, 2018 - Green filters increase reading speed for children with dyslexia
October 19, 2018 - Bariatric Sx Cuts Macrovascular Complications in Obesity, T2DM
October 19, 2018 - Better assessments for early age-related macular degeneration
October 19, 2018 - Visible and valued: Stanford Medicine’s first-ever LGBTQ+ Forum | News Center
October 19, 2018 - Understanding of metal-free enzymes used by bacteria could lead to new effective antibiotics
October 19, 2018 - Beckman Coulter Life Sciences announces new research-focused website
October 19, 2018 - Study finds link between refined soluble fibers, gut microbiota and liver cancer
October 19, 2018 - Social media reduces risk of depression among seniors with pain
October 19, 2018 - Newly developed synthetic DNA molecule may one day be used as ‘vaccine’ for prostate cancer
October 19, 2018 - Preoperative weight loss may not provide health benefits after surgery
October 19, 2018 - U.S. Birth Rates Continue to Drop as Age of New Moms Rises
October 19, 2018 - New technology can keep an eye on babies’ movements in the womb
October 19, 2018 - Juul e-cigarettes pose addiction risk for young users | News Center
October 19, 2018 - Gene sequencing reveals crucial molecular aspects of Trypanosoma brucei
October 19, 2018 - New DNA vaccine strategy protects mice against lethal challenge by multiple H3N2 viruses
October 19, 2018 - Study shows close link between cytokine interleukin-1ß and obesity-promoted colon cancer
October 19, 2018 - Muscle mass plays a critical role in health, shows research
October 19, 2018 - Study finds undiagnosed prediabetes in many infertile men
October 19, 2018 - The Current issue of “The view from here” is concerned with Nanotherapeutic strategies
October 19, 2018 - Delay in replacing the Pap smear with HPV screening is costing lives
October 19, 2018 - Physicians battle pediatric diseases of ear, nose, throat in Zimbabwe | News Center
October 19, 2018 - Researchers investigate why some cancers affect only young women
October 19, 2018 - Drugmakers funnel millions to lawmakers; a few dozen get $100,000-plus
October 19, 2018 - Unselfish people tend to have more children and receive higher salaries
October 19, 2018 - New findings reveal potential cellular players in tumor microenvironment
October 19, 2018 - Study reveals impact of Juul use on teenagers and young adults
October 19, 2018 - Green leafy vegetables could help reduce macular degeneration risk
October 19, 2018 - Some countries take more time for reimbursement decisions on new cancer drugs
October 19, 2018 - Human brain cell transplant offers insights into neurological conditions
October 19, 2018 - Parental education associated with increased family health care spending
October 19, 2018 - New statistical method estimates long- and short-term risk of recurrence of breast cancer in US women
October 19, 2018 - Father’s exposure to nicotine may cause cognitive deficits in descendants
October 19, 2018 - Could we prevent Alzheimer’s disease by treating herpes?
October 19, 2018 - Nurse-led care can be more successful in managing gout
October 19, 2018 - Trump administration, pharma exchange verbal volleys on drug-price transparency
Large ALS-causing protein aggregates protect rather than harm neurons

Large ALS-causing protein aggregates protect rather than harm neurons

image_pdfDownload PDFimage_print

Scientists at the UNC School of Medicine have made a significant advance in the understanding of the complex and fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.

Autopsy studies of ALS patients often reveal the accumulation of large, fibrous aggregates of a protein called SOD1 in disease-affected motor neurons. Researchers have hypothesized that these fibrils are what kill neurons and cause ALS in some people. But in a study published in the Proceedings of the National Academy of Sciences, scientists at the University of North Carolina at Chapel Hill found evidence that these large SOD1 fibrils protect rather than harm neurons.

“This is potentially an important finding not only for ALS research but for neurodegenerative disease research in general, because the formation of fibril aggregates is so common in these diseases,” said senior author Nikolay Dokholyan, PhD, the Michael Hooker Distinguished Professor of Biochemistry and Biophysics at UNC-Chapel Hill.

Large, often fibril-type protein aggregates are in fact the most obvious pathological features of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, and other major neurodegenerative diseases. Many of the candidate drugs developed in recent years were designed to clear these protein aggregates. But none of these fibril-targeting strategies have proven effective in large clinical trials. Laboratory studies also have largely failed to prove that large SOD1 fibrils are harmful to neurons.

At the same time, researchers have found that much smaller protein clusters called oligomers – made of only a few copies of these proteins – can be highly toxic to motor neuron-like cells grown in the lab and thus are more likely to be the chief causes of brain-cell death in these diseases.

In a 2016 study, for example, Dokholyan’s lab found evidence that “trimer” structures made of just three copies of the SOD1 protein are toxic to the type of neuron affected in ALS.

For the new study, Dokholyan’s team, including lead author Cheng Zhu, PhD, a postdoctoral researcher in his lab, conducted complicated experiments to compare how trimers affect neurons to how larger fibrils affect neurons.

“One challenge is that the smaller structures such as trimers tend to exist only transiently on the way to forming larger structures,” Zhu said. “But we were able to find an SOD1 mutation that stabilizes the trimer structure and another mutation that promotes the creation of the larger fibrils at the expense of smaller structures. So, we were able to separate the effects of these two species of the protein.”

The researchers expressed the mutant SOD1 proteins in test cells that closely resemble the muscle-controlling neurons killed in ALS. They found – as they did in the 2016 study – that when these cells expressed SOD1 mutants that predominantly form trimers, the cells died much more quickly than control cells containing normal SOD1. The trimer-expressing cells even died more quickly than cells expressing mutant forms of SOD1 that are found in severe hereditary ALS cases.

“Looking at various SOD1 mutants, we observed that the degree of toxicity correlated with the extent of trimer formation,” Zhu said.

On the other hand, the viability of cells containing mutant SOD1 that strongly forms fibrils but suppresses trimers tended to be similar as wild-type SOD1, suggesting that the fibrils are protective, not merely less toxic.

This suggests SOD1 fibrils aren’t the problem in SOD1-linked ALS; they might be a solution. “Taking a drug to promote fibril formation could be one way to reduce toxicity in SOD1-ALS,” Dokholyan said.

An alternative strategy, he noted, would be to limit the formation of trimers or other small, toxic SOD1 oligomers. SOD1 normally works in cells as a two-copy structure, a dimer. Trimers and other abnormal structures appear to originate when the dimers fall apart. So Dokholyan and colleagues are looking for potential drug molecules that can stabilize the dimers.

SOD1 is linked to a significant proportion of ALS cases. Mutations in the SOD1 gene account for about 12 percent of ALS cases that run in families. All of these mutations destabilize the protein’s normal structure and promote abnormal SOD1 structures. SOD1 mutations also appear to account for about 1.5 percent of cases that do not obviously run in families.

“Although SOD1-associated ALS represents a small fraction of all ALS cases, uncovering the origins of neurotoxicity in SOD1 aggregation may shed light on the underlying causes of an entire class of neurodegenerative diseases,” Dokholyan said.

The next steps for Dokholyan’s lab is to pinpoint downstream cellular mechanisms of toxicity of pathological trimeric SOD1 and find drugs that mitigate the formation of trimers.

Source:

https://www.unchealthcare.org/

Tagged with:

About author

Related Articles