Monthly Archives: January 2015

HOUSTON -- (Jan. 15, 2015) - Alteration of lipid metabolism in brain cells promotes the formation of lipid droplets that presage the loss of neurons, said researchers from Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital in a report that appears online in the journal Cell.

Neuroscience graduate student Lucy Liu, and Dr. Hugo Bellen, professor of molecular and human genetics, neuroscience, a Howard Hughes Medical Institute investigator and director of the Graduate Program in Developmental Biology at Baylor connected the presence of lipid droplet accumulation in the glia of specific mutants as a harbinger of neurodegeneration.

Fruit fly genetics

The Bellen lab uses fruit fly mutants of evolutionarily conserved genes that lead to neurodegeneration in human patients to dissect the molecular mechanisms that underlie the demise of neurons. The fruit flies carry mutations in genes that have human homologs that cause Leigh syndrome, Charcot-Marie-Tooth type 2A2 and ARSAL (autosomal recessive spastic ataxia with leukoencephalopathy). All of these mutations affect the function of the mitochondria, the powerhouse of the cell.

Lipid droplets and energy

Lipid droplets are organelles that serve as energy storage depots. They accumulate in the brain support cells (glia) when defects in the mitochondria of neurons lead to elevated levels of reactive oxygen species (ROS). Working with three independent fruit fly models and a mouse model, Liu et al., revealed a novel pathway leading to this accumulation through the inappropriate activation of two proteins: c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP). These lipid droplets accumulate in glial cells before signs of neurodegeneration appeared.

"This is the first documentation of lipid droplet accumulation in glial cell" said Liu, first author of the study. The authors show that elevated reactive oxygen species in the neurons promotes synthesis of lipids leading to the formation of lipid droplets in glia. This accumulation affects the glia's ability to support the neurons when the lipid droplets become peroxidated, completing a negative feedback loop.

Not enough for neurodegeneration

"ROS or lipid droplets alone do not lead to the rapid onset of neurodegeneration," said Bellen, senior author on the study. "The synergism of ROS with lipid droplets is key. Reducing one or the other delays neurodegeneration."

Upon further investigation, Liu and her colleagues showed that reducing many of the components of this pathway can delay neurodegeneration. For example, treatments with a blood-brain-barrier penetrating antioxidant delay the onset of neurodegeneration in flies and mice developed by their collaborator Dr. Albert Quintana at University of Washington in Seattle.

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Baylor College of Medicine scientist identify a novel precursor to neurodegeneration

Largest study to date of rare genetic variants and asthma risk finds few associations

Despite a strong suspected link between genetics and asthma, commonly found genetic mutations account for only a small part of the risk for developing the disease - a problem known as missing heritability.

Rare and low frequency genetic mutations have been thought to explain missing heritability, but it appears they are unlikely to play a major role, according to a new study led by scientists from the University of Chicago. Analyzing the coding regions of genomes of more than 11,000 individuals, they identified mutations in just three genes that were associated with asthma risk. Each was associated with risk in specific ethnicities. Their findings, published in Nature Communications on Jan. 16, suggest gaps in the current understanding of asthma genetics.

"Previous studies have likely overestimated the heritability of asthma," said study senior author Carole Ober, PhD, Blum-Riese Professor and chair of the Department of Human Genetics at the University of Chicago. "This could be because those estimates are based on correlations between family members that share environment as well as genes, which could inflate the heritability. Gene-environment interactions are not considered in these large scale association studies, and we know that these are particularly important in establishing individual risks for asthma."

Asthma affects more than 25 million adults and children of all ages and ethnicities in the US. Due to the widespread nature of the disease, most studies of its genetic underpinnings have focused on commonly occurring mutations, referred to as genetic variants. However, while numerous such variants have been identified, they are able to account for only a small proportion of the risk for inheriting or developing asthma. Rare mutations, found in less than five percent of the population, have been hypothesized to explain this disparity.

Graduate student Catherine Igartua led the analysis under the supervision of co-senior author Dan Nicolae, PhD, Professor in the Departments of Medicine, Statistics and Human Genetics. She evaluated nearly 33,000 rare or low frequency mutations in more than 11,000 individuals of a variety of ethnicities representing European, African and Latino backgrounds. She analyzed mutations jointly across subjects, using a technique that allowed them to study mutations common in one ethnicity, but rare in others.

Only mutations in the genes GRASP, GSDMB and MTHFR showed a statistical link to asthma risk. Mutations in the first two genes were found primarily in Latino individuals, and mutations in the last gene in those with African ancestry. These genes, involved in protein scaffolding, apoptosis regulation and vitamin B9 metabolism respectively, have as yet unknown roles in asthma. The rarity and ethnic-specificity of these genes is insufficient to account for the widespread prevalence of asthma.

Although rare mutations might not contribute much to population asthma risk, these genes still have the potential to serve as targets for therapeutic development. Ober points to the discovery of rare mutations in the LDL receptor that eventually led to the development of statins to treat high cholesterol. She also notes that it is possible, but unlikely, that there are mutations with large effects on asthma risk outside of their screen as it looked at approximate 60 percent of mutations in coding regions of the genome.

"It was assumed that there would be rare mutations with larger effect sizes than the common variants we have been studying," Ober said. "Surprisingly, we found that low frequency mutations explain only a very small amount of asthma risk."

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Rare mutations do not explain 'missing heritability' in asthma