Breaking News
March 25, 2019 - Benefits of osteoporosis treatment in postmenopausal women outweigh the perceived risks
March 25, 2019 - Researchers find evidence of Cryptosporidium parasite in Minnesota’s public water systems
March 25, 2019 - Three Clues to Raised Risk of Miscarriage
March 25, 2019 - Structured play helps toddlers self-regulate, altering their life course
March 25, 2019 - Translating horror into justice: Stanford psychiatrist advocates for human rights
March 25, 2019 - HORIBA Medical introduces D-Dimer reagent for Yumizen G hemostasis range
March 25, 2019 - Recurrent pregnancy loss may be caused by sperm DNA damage, finds study
March 25, 2019 - Special Collection tracks development of new diagnostic tests for tuberculosis
March 25, 2019 - Air Force develops genetic test to predict mental performance
March 25, 2019 - To abort or not to abort—making difficult choices alone
March 25, 2019 - Computer vision technology could aid ICU care by spotting movement
March 25, 2019 - IONTAS wins ‘Small Business of the Year’ category at Cambridge News Business Excellence Awards 2019
March 25, 2019 - First postpartum depression drug gets FDA nod
March 25, 2019 - Research Recognition Award will help improve lives of young people with absence epilepsy
March 25, 2019 - Bisphosphonates to treat osteoporosis appears to be beneficial for all women
March 25, 2019 - Dolomite Bio releases new Drop-seq datasets for single-cell RNA sequencing
March 25, 2019 - Hemoglobin A1c blood test may underestimate prevalence of diabetes
March 25, 2019 - Eating leafy green vegetables may help maintain muscle strength and mobility
March 25, 2019 - BMA secures state-backed clinical negligence indemnity scheme for GP trainees
March 25, 2019 - Biohaven Announces Completion of Pre-NDA Meeting With FDA for Oral CGRP Receptor Antagonist Rimegepant
March 25, 2019 - Adding breakfast to classrooms may have a health downside
March 25, 2019 - She Was Dancing On The Roof And Talking Gibberish. A Special Kind Of ER Helped Her.
March 25, 2019 - KNAUER introduces new Sepapure FPLC columns and media for protein purification tasks
March 25, 2019 - Weight loss in obese migraine sufferers can improve their quality of life
March 25, 2019 - Exposure to particulate air pollution may lead to reduced sperm production
March 25, 2019 - Synthetic peptide appears to disrupt inflammation and protect kidneys from nephritis
March 25, 2019 - New guideline focuses on strategies to improve health of older adults with diabetes
March 25, 2019 - Study evaluates prescribing of preventive drugs at the end of life in older adults with cancer
March 25, 2019 - Radial or femoral approaches for PCI are equal in terms of survival in heart attack patients
March 25, 2019 - Study shows how some autoimmune diseases are more closely related than others
March 25, 2019 - Long term opioid medications impacts production of important hormones
March 25, 2019 - FDA Issues Complete Response Letter for Zynquista (sotagliflozin)
March 25, 2019 - CDC researchers report on trends in hospital breastfeeding policies
March 25, 2019 - States Push For Caregiver Tax Credits
March 25, 2019 - Females on ketogenic diet fail to show metabolic benefits in animal model
March 25, 2019 - Modulating stiffness of blood-forming stem cells could facilitate mobilization procedures
March 25, 2019 - Gene editing regulations to be tightened
March 25, 2019 - CPAP treatment can result in weight loss in people with sleep apnea and obseity
March 25, 2019 - Highly attractive businesswomen are considered less trustworthy ‘femmes fatales’
March 25, 2019 - Breast Density Categorization Varies With Screening Modality
March 25, 2019 - Researchers explore link between metal exposure and Parkinson’s symptoms
March 25, 2019 - Later meal timing may contribute to weight gain
March 25, 2019 - Around one in hundred people has autism spectrum condition in China
March 25, 2019 - Research paves way for new standard of care to improve heart’s pump function
March 25, 2019 - Exposure to HIV virus, antiretroviral therapy before birth linked to obesity and asthma-like symptoms
March 25, 2019 - Transgender men preserve their fertility potential after one year of testosterone therapy
March 25, 2019 - Tighter Blood Pressure Control May Prevent Brain Lesions
March 25, 2019 - A reward now or later? Exploring impulsivity in Parkinson’s disease patients
March 25, 2019 - Financial incentives fail to increase completion rates of colorectal cancer screening tests mailed to patients
March 25, 2019 - New research program launched to highlight sexual harassment in academia
March 25, 2019 - Hemoglobin A1c blood test does not detect diabetes in most patients, shows study
March 25, 2019 - Wyss Technology licensed by Sherlock Biosciences to create affordable molecular diagnostics
March 25, 2019 - DWK Life Sciences launches KIMBLE GLS 80 Media Bottle and Multiport Cap System
March 25, 2019 - New study aims to reduce online sexual exploitation of children
March 25, 2019 - Want healthier eating habits? Start with a workout
March 25, 2019 - New approach to prescribing antibiotics could curb resistance
March 24, 2019 - Theravance Biopharma Announces First Patient Dosed in Phase 2b/3 Study of TD-1473 in Patients with Ulcerative Colitis
March 24, 2019 - Prenatal DHA prevents blood-pressure increase from obesity during childhood
March 24, 2019 - Combined immunosuppression may be effective, safe in treating older patients with Crohn’s disease
March 24, 2019 - GSK sells health drinks arm, buys US cancer treatment firm
March 24, 2019 - Bacteria and innate immune factors in birth canal, cervix may be key to predicting preterm births
March 24, 2019 - IgG antibodies play unexpected role in atherosclerosis
March 24, 2019 - Sounds and vibrations are quite similar for the brain, finds new study
March 24, 2019 - Practices for Reducing COPD Hospital Readmissions Explored
March 24, 2019 - Could an eye doctor diagnose Alzheimer’s before you have symptoms?
March 24, 2019 - Enzyme inhibitor stops inflammation and neurodevelopmental disorders in mouse models
March 24, 2019 - Walk, Dance, Clean: Even a Little Activity Helps You Live Longer
March 24, 2019 - Americans used less eye care in 2014 versus 2008
March 24, 2019 - Study finds link between depression in 20s linked to memory loss in 50s
March 24, 2019 - New tool helps physiotherapy students to master complex fine motor skills
March 24, 2019 - The AMR Centre secures £2.3m funding boost
March 24, 2019 - Study examines effects of taking ondansetron during first trimester of pregnancy
March 24, 2019 - Researchers identify a more effective treatment for cancer
March 24, 2019 - Open-source solution for multiparametric optical mapping of the heart’s electrical activity
March 24, 2019 - New nanotechnology approach shows promise in treating triple negative breast cancer
March 24, 2019 - Trevena Announces Publication of APOLLO-1 Results in The Journal of Pain Research Highlighting Oliceridine’s Potential for Management of Moderate-to-Severe Acute Pain
March 24, 2019 - Maternal deaths following C-section 50 times higher in Africa compared to high-income countries
March 24, 2019 - Apple watch could detect irregular heart beat says study
March 24, 2019 - Queen Mary University of London’s BCI boosts radionuclide imaging capabilities with MILabs VECTor technology
March 24, 2019 - Girls should be encouraged to gain more ball skills, shows study
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