Most children with the inherited disease ataxia telangiectasia are wheelchair-bound by age 10 because of neurological problems. Patients also have weakened immune systems and more frequent leukemias, and are more sensitive to radiation.

The underlying problem comes from mutations in the ATM (ataxia telangiectasia mutated) gene, which encodes an enzyme that controls cells' response to and repair of DNA damage.

ATM can be turned on experimentally by treating cells with chemicals that damage DNA. After other proteins in the cell detected broken DNA needing repair, scientists had thought that the ATM protein could activate itself directly. Emory researchers have shown that an additional step is necessary first.

"In neurons that are not dividing anymore, we now know that another regulator is involved: Cdk5," says Zixu Mao, MD, PhD, associate professor of pharmacology and neurology at Emory University School of Medicine.

Working with postdoctoral fellows Bo Tian, PhD and Qian Yang, PhD, Mao found that the Cdk5 protein must activate ATM before ATM can do its job in neurons.

The results support the idea that Cdk5 may be a potential drug target. Cdk5 contributes to normal brain development, and aberrant Cdk5 activity is known to be involved in the death of neurons in several neurodegenerative diseases, including Alzheimer's, Parkinson's and amyotrophic lateral sclerosis.

"Cdk5 has a complex character," Mao says. "It can be bad for neurons if its activity is either too high or too low."

Mao says he and his colleagues were intrigued by reports that in these diseases, neurons that had stopped dividing appear to restart that process, copying their DNA, before dying.

"That's what really kicked us into high gear," he says.

The same process, called "mitotic catastrophe," occurs when neurons suffer DNA damage. Inhibiting either Cdk5 or ATM can reduce the number of neurons that suffer mitotic catastrophe after DNA damage, the authors found.

emory

The team's study is the first molecular survey of gut microbial diversity following surgical weight loss, and has helped solidify the link between methane producing microbes and obesity. Specifically, the microbial populations extracted from obese individuals were high in a particular microbial subgroup, hydrogen-producing bacteria known as prevotellaceae. Further, such hydrogen producers appear to coexist with hydrogen-consuming methanogens, found in abundance in obese patients, but absent in both normal weight and gastric bypass samples. Unlike the hydrogen producers, however, these methane-liberating hydrogen consumers are not bacteria. They belong instead to the third great microbial domain ”the Archaea, (with Eukarya and Bacteria making up the other two).

Energy managers

During the course of digestion, calories are extracted from food and stored in fat tissue for later use ”a process delicately regulated by the multitude of microbial custodians. The intermediary products of the digestive process include hydrogen, carbon dioxide and several short chain fatty acids (SCFAs).

Results suggest a cooperative co-existence in obese individuals between hydrogen-producers and hydrogen consuming methanogens. Rittmann explains how this mutually reinforcing relationship, known as syntrophy, may contribute to obesity:

"Organisms producing hydrogen and acetate create a situation like cars flooding onto the highway. The methanogens, which remove the hydrogen, are like the offramps, allowing the hydrogen cars to get off. That allows more acetate cars to get on, because some hydrogen cars are coming off the highway."

The methanogen offramps, by removing hydrogen, accelerate the efficient fermentation of otherwise indigestible plant polysaccharides and carbohydrates. The effect is to boost production of SCFAs, particularly acetate, which will be taken up by the intestinal epithelium and converted to fat. The result over time may be increasing weight, eventually leading to obesity.

While weight regulation involves a complex interplay of genetic predisposition, exercise, eating habits, and other factors, manipulation of the gut's microflora, particularly the methanogenic Archaea, may provide additional avenues for the treatment of morbid obesity.

The researchers stress that the study is preliminary, but were encouraged by the findings from their small sample. Future investigation is needed to establish the differences in composition of gut microbiota across different age groups and under varying weight-loss regimens involving diet and exercise. Nevertheless, the study's findings point to new avenues for modifying the body's energy harvesting efficiency ”perhaps by manipulation of the Bacteria-Archaea nexus.

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