Breaking News
January 24, 2019 - Good health literacy linked to better adherence to blood pressure medications among Hispanics
January 24, 2019 - Only a minority of patients in the U.S. with type 1 diabetes achieve treatment goals
January 24, 2019 - High fat reduces efficiency of the immune system to fight infectious disease
January 24, 2019 - Study highlights need for reliable therapeutic targets for prevention, treatment of cardiovascular diseases
January 24, 2019 - Next step toward replacement therapy in type 1 diabetes
January 24, 2019 - “Scientific serendipity” identifies link between type of RNA and autism
January 24, 2019 - Trump Zeroes In On Surprise Medical Bills In White House Chat With Patients, Experts
January 24, 2019 - Unique form of chronic sinusitis found in older patients
January 24, 2019 - NUS researchers make muscle recovery easier for patients with ingenious medical device
January 24, 2019 - Specific cognitive deficits found in individuals with spinal cord injury
January 24, 2019 - An essential reference for diagnostic ultrasonography and biopsy of the thyroid gland
January 24, 2019 - Proteus Digital Health Launches Digital Oncology Medicines to Improve Patient Outcomes
January 24, 2019 - Study looking to prevent type 1 diabetes follows children into adolescence
January 24, 2019 - Nice doctors make a difference
January 23, 2019 - Blood vessel discovery could advance our knowledge of osteoporosis
January 23, 2019 - New esophageal cancer test uses genetic biomarkers to detect changes in esophagal cells
January 23, 2019 - Study evaluates first-ever Robotic Visualization System for neurosurgery
January 23, 2019 - Scientists reveal new mechanism that could lead to specific treatment of strokes and seizures
January 23, 2019 - Both educational level and occupational orientation predict mother’s smoking during pregnancy
January 23, 2019 - How to (gently) get your child to brush their teeth
January 23, 2019 - Short-term hospital readmissions for gun injuries cost $86 million a year | News Center
January 23, 2019 - New certified reference material for testing residual solvents in cannabis
January 23, 2019 - Gene-edited chickens could prevent future flu pandemic
January 23, 2019 - Cardiovascular disease risk begins even before birth
January 23, 2019 - Younger patients receiving kidney transplant more likely to live longer, shows data
January 23, 2019 - Skin samples hold early signs of prion disease, research suggests
January 23, 2019 - Researchers discover how body initiates repair mechanisms that limits damage to myelin sheath
January 23, 2019 - Fecal transplant from certain donors better than others
January 23, 2019 - Risk for Uninsurance in AMI Patients Reduced With Medicaid Expansion
January 23, 2019 - Readmissions reduction program may be associated with increase in patient-level mortality
January 23, 2019 - Fostering translation and communication in medicine and beyond
January 23, 2019 - To Fight Fatty Liver, Avoid Sugary Foods and Drinks
January 23, 2019 - TPU scientists develop new implants that double the rate of bone lengthening in kids
January 23, 2019 - New sessions at Pittcon 2019
January 23, 2019 - Insilico to present latest findings in AI for Drug Discovery at 3rd Annual SABPA FTD Forum
January 23, 2019 - Opioid overdose patients can be safely discharged an hour after administration of naloxone
January 23, 2019 - Scientists find bacterial extracellular vesicles in human blood
January 23, 2019 - Researchers use modified type of flu virus to develop new therapies for prostate cancer
January 23, 2019 - Researchers gain new insights into development of necrotizing enterocolitis in preemies
January 23, 2019 - Medical expert advises people with epilepsy not to stockpile medicines
January 23, 2019 - CDC study explores link between smoking and clinical outcomes of assisted reproductive technology
January 23, 2019 - Study outlines research priorities for improving pediatric patient care and safety
January 23, 2019 - Bedfont to exhibit NObreath FeNO monitor at Arab Health 2019
January 23, 2019 - Nicotinamide riboside supplementation confers significant physiological benefits to mothers and offspring
January 23, 2019 - Increasing temperatures may help preserve crop nutrition
January 23, 2019 - Many Oncologists in the Dark About LGBTQ Health Needs
January 23, 2019 - Epigenetic change causes fruit fly babies to inherit diet-induced heart disease
January 23, 2019 - Erasing memories could reduce relapse rates among drug addicts
January 23, 2019 - African Americans who smoke cigarettes are more likely to develop peripheral artery disease
January 23, 2019 - Unique data combination helps FinnGen researchers to fund links between genetic factors and health
January 23, 2019 - Parents’ mental health problems associated with reactive attachment disorder in children
January 23, 2019 - Graphene Flagship project studies impact of graphene and related materials on our health
January 23, 2019 - The connection between the Pope and contraceptive pills
January 23, 2019 - Prior dengue infection could protect children from symptomatic Zika
January 23, 2019 - Previous dengue virus infection associated with protection from symptomatic Zika
January 23, 2019 - VISTA checkpoint implicated in pancreatic cancer immunotherapy resistance
January 23, 2019 - The Tiny Camera That Could Revolutionize Cardiovascular Surgery
January 23, 2019 - Peptide isolated from soil fungi has antitumor and antibacterial properties
January 23, 2019 - TGen identifies polio-like virus as potential cause of Acute Flaccid Myelitis outbreak
January 23, 2019 - Migrants and refugees do not bring disease and are at greater health risk themselves says WHO
January 23, 2019 - Examing the effects of menopause in workplace
January 23, 2019 - Enemy number 1 – Air pollution and climate change top of WHO agenda
January 23, 2019 - Two Positive Phase III studies of Tafenoquine for the Radical Cure of Plasmodium vivax Malaria Published in The New England Journal of Medicine
January 23, 2019 - World Trade Center responders at increased risk for head and neck cancers
January 23, 2019 - Low-sugar diet leads to significant improvement in nonalcoholic fatty liver disease in boys
January 23, 2019 - Chaos in bodily regulation can optimize our immune system, finds study
January 23, 2019 - Short, text-based exercises can increase happiness for adults recovering from substance use disorders
January 23, 2019 - Body size may have greater influence on women’s lifespan than men
January 23, 2019 - Groundbreaking tool helps visualize neuronal activity with near-infrared light
January 23, 2019 - Prior dengue immunity in children may be protective against symptomatic Zika
January 23, 2019 - Holocaust survivors with PTSD and their offspring exhibit more unhealthy behavior patterns
January 23, 2019 - Scientists discover new genetic mutations causing inherited deaf-blindness
January 23, 2019 - UC team designs new naloxone-dispensing smart device
January 23, 2019 - Torrent Pharmaceuticals Limited Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP and Losartan Potassium and Hydrochlorothiazide Tablets, USP
January 23, 2019 - Brain activity shows development of visual sensitivity in autism
January 23, 2019 - Two hour gap between dinner and sleep is overrated says Japanese research
January 23, 2019 - Fear and embarrassment are causing smear test numbers to plummet
January 23, 2019 - Protein-secreting device implanted in epileptic rats reduces seizures, improves cognition
January 23, 2019 - Reintroduction project recovers current wild population of green turtle in Cayman Islands
January 23, 2019 - Cancer survivors face greater financial burden related to medical bills
Genetic defect linked to ALS causes sugar-starved cells to overproduce lipids

Genetic defect linked to ALS causes sugar-starved cells to overproduce lipids

image_pdfDownload PDFimage_print

A genetic defect tied to a variety of neurodegenerative diseases and mental illnesses changes how cells starved of sugar metabolize fatty compounds known as lipids, a new study led by researchers from the Johns Hopkins Bloomberg School of Public Health shows. The finding could lead to new targets to treat these diseases, which currently have no cure or fully effective treatments.

Taken together, these results suggest that the genetic defect, mutations in a gene called C9orf72, lead to greater amounts of a protein that causes cells to overproduce lipids and an enzyme called NOX2. The enzyme NOX2, which is known to cause oxidative stress that can damage cells, has also been shown to be elevated in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.

The findings were published online Oct. 26 in the journal Genes & Development.

“Cells with this mutation act as if they’re chronically under stress, which could underlie the pathology of diseases associated with this defect,” says Jiou Wang, MD, PhD, an associate professor in the Bloomberg School’s Department of Biochemistry and Molecular Biology. “Our study raises the question of whether we should be looking at problems with lipid metabolism as a potential cause for these diseases.”

Researchers identified the mutation in the C9orf72 gene several years ago, and it has since been associated with ALS, frontotemporal dementia, Alzheimer’s disease and bipolar disorder, and other neurologic diseases. Although researchers have known that this mutation decreases the amount of the protein coded by the C9orf72 gene in cells, it was unknown exactly what this C9orf72-coded protein does.

To learn its function, the researchers created mouse cells in which C9orf72 was effectively removed, preventing the production of its protein in order to study what happens in cells naturally carrying the gene’s mutated form. They then compared these cells to those with the gene, looking broadly at the levels of all proteins produced in both types of cells. They studied these protein levels both under normal conditions as well as when the cells lived in environments devoid of the sugar known as glucose, an important cellular energy source. Previous studies have hinted, Wang explains, that C9orf72 might play a role in how cells protect themselves from nutrient starvation stress.

When healthy cells are deprived of glucose, Wang says, they tend to make and store more lipid droplets. However, the researchers’ protein level analysis showed that when deprived of glucose, the cells lacking the C9orf72 protein produced significantly more lipid metabolism-related proteins compared to cells with this gene. When the researchers compared the number of lipid droplets between the two types of cells in glucose-devoid conditions, the cells lacking C9orf72 protein held significantly more. They also had more free fatty acids, the individual components that come together to form these lipid droplets.

To better understand why lipids increased in cells without the C9orf72 gene, the researchers looked at the two different pathways that cells use to create lipid droplets: either creating them from scratch, a process called de novo lipid biogenesis, or by digesting other components of the cell to make lipids, a process called autophagy. They found higher amounts of the proteins associated with both routes in cells without the C9orf72 gene, suggesting that each lipid-producing pathway was abnormally regulated.

Digging even deeper to find out how cells without C9orf72 boosted both pathways, they did another protein analysis to find which proteins are associated with C9orf72. Their search led them to CARM1, a protein known to broadly affect which genes produce proteins, and how much. It turns out that C9orf72 is important for a previously unknown pathway to degrade the CARM1 protein by the lysosome, the cell’s digestive organelle. Further investigation showed that in C9orf72 knockout cells, CARM1 levels increase, leading to greater expression of genes related to lipid production.

To see if these results translate to what happens in patients with C9orf72 mutations, the researchers studied cells and tissues from patients with ALS and frontotemporal dementia. Starving these samples of glucose led to the same results they saw in the mouse-derived cells: increased lipid levels caused by dysregulation of both lipid-producing pathways, along with increased levels of CARM1 and NOX2.

Taken together, Wang says, these results suggest that mutations in C9orf72 lead to greater amounts of CARM1, which causes cells to overproduce lipids and NOX2 in response to glucose starvation.

“As we learn more about this newly discovered biological pathway,” says Wang, “it could lead to new therapeutic interventions that protect cells that carry this mutation from harm.”

“A C9orf72-CARM1 Axis Regulates Lipid Metabolism Under Glucose Starvation-induced Nutrient Stress,” by Yang Liu, Tao Wang, Yon Ju Ji, Kenji Johnson, Honghe Liu, Kaitlin Johnson, Scott Bailey, Yongwon Suk, Yu Ning Lu, Mingming Liu and Jiou Wang.

Source:

https://www.jhsph.edu/news/news-releases/2018/mutation-associated-with-ALS-causes-sugar-starved-cells-to-overproduce-lipids-study-shows.html

Tagged with:

About author

Related Articles