Nothing he tried had worked. For Sigurjon Jakobsson, the trip to Atlanta with his family was a last-ditch effort to wake up. He had struggled with sleeping excessively for several years before coming from Iceland to see a visionary neurologist, who might have answers.
In high school, Sigurjon was a decathlete competing as part of Iceland’s national sports team. But at the age of 16, an increasing need for sleep began to encroach upon his life. Read more
New research in mice strengthens a potential strategy for treating fragile X syndrome, the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorder.
The results, published April 23 inÂ Cell Reports, suggest that a drug strategy targeting a form of the enzyme PI3 (phosphoinositide-3) kinase could improve learning and behavioral flexibility in people with fragile X syndrome. The PI3 kinase strategy represents an alternative to one based on drugs targeting mGluR5 glutamate receptors, which have had difficulty showing benefits in clinical trials.
Research led by Emory scientistsÂ Gary Bassell, PhD and Christina Gross, PhD had previously found that the p110Î² form of PI3 kinase is overactivated in the brain in a mouse fragile X model, and in blood cells from human patients with fragile X syndrome.
Now they have shown that dialing back PI3 kinase overactivation by using genetic tools can alleviate some of the cognitive deficits and behavioral alterations observed in the mouse model. Drugs that target the p110Î² form of PI3 kinase are already in clinical trials for cancer.
“Further progress in this direction could lead to a clinical trial in fragile X,” says Bassell, who is chair of Cell Biology at Emory University School of Medicine. “The next step is to test whether this type of drug can be effective in the mouse model and in human patient cells.” Read more
A new paper in PNAS from geneticist Steve Warren and colleagues illustratesÂ the complexity of the protein disrupted in fragile X syndrome. It touches on how proposed drug therapies that address one aspect of fragile X syndrome may not be able to compensate for all of them. [For a human side of this story, read/listen to this recent NPR piece from Jon Hamilton.]
Fragile X syndrome is the most common single-gene disorder responsible for intellectual disability. Most patients with fragile X syndrome inherit it because a repetitive stretch of DNA, which is outside the protein-coding portion of the fragile X gene, is larger than usual. The expanded number of CGG repeats silences the entire gene.
However, simple point mutations affecting the fragile X protein are possible in humans as well. In the PNAS paper, Warren’s team describes what happens with a particularly revealing mutation, which allowed researchers to dissect fragile X protein’s multifaceted functions. Read more
The fragile X protein — missing in the most common inherited form of intellectual disability — plays a central role in neurons and how they respond to external signals.Â Cell biologist Gary Bassell and his colleagues have been examining how the fragile X protein (FMRP) acts as a “toggle switch.”
Gary Bassell, PhD
FMRP controls the activity of several genes by holding on to the RNAs those genes encode. When neurons get an electrochemical signal from the outside, FMRP releases the RNAs, allowing the RNAs to be made into protein, and facilitating changes in the neurons linked to learning and memory.
The Bassell lab’s new paper in Journal of Neuroscience reveals the role of another player in this process. The first author is postdoctoral fellow Vijay Nalavadi.
The researchers show that neurons modify FMRP with ubiquitin, the cellular equivalent of a tag for trash pickup, after receiving an external signal. In general, cells attach ubiquitin to proteins so that the proteins get eaten up by the proteasome, the cellular trash disposal bin. Here, neurons are temporarily getting rid of FMRP, prolonging the effects of the external signal.
An article in the April 2011 issue of Nature Medicine highlights the mechanistic overlap between autism and epilepsy.
By studying how rare genetic conditions known to coincide with both epilepsy and autismâ€”such as Rett syndrome, fragile X syndrome and tuberous sclerosisâ€”unfold at an early age, neuroscientists are finding that both disorders may alter some of the same neural receptors, signaling molecules and proteins involved in the development of brain cell synapses.
Gary Bassell, PhD
Emory cell biologist Gary Bassell and his colleagues have been taking exactly this approach. Recently they published a paper in Journal of Neuroscience, showing that the protein missing in fragile X syndrome, FMRP, regulates expression of an ion channel linked to epilepsy. This could provide a partial explanation for the link between fragile X syndrome and epilepsy.
The Nature Medicine article also mentions a drug strategy, targeting the mTOR pathway, which Bassell’s group has been exploring with fragile X syndrome.
If the brain acts like a computer, which of the brain’s physical features store the information? Flashes of electricity may keep memories and sensations alive for the moment, but what plays the role that hard drives and CDs do for computers?
A simple answer could be: genes turning on and off, and eventually, neurons growing and changing their shapes. But it gets more complicated pretty quickly. Genes can be regulated at several levels:
at the level of transcription — whether messenger RNA gets made from a stretch of DNA in the cell’s nucleus
at the level of translation — whether the messenger RNA is allowed to make a protein
at the level of RNA localization — where the mRNAs travel within the cell
Each neuron has only two copies of a given gene but will have many dendrites that can have more or less RNA in them. That means the last two modes of regulation offer neurons much more capacity for storing information.
Gary Bassell, a cell biologist at Emory, and his colleagues have been exploring how RNA regulation works in neurons. They have developed special tools for mapping RNA, and especially, microRNA — a form of RNA that regulates other RNAs.
In the dendrites of neurons, FMRP seems to control where RNAs end up
Fragile X mental retardation protein (FMRP), linked to the most common inherited form of mental retardation, appears to orchestrate RNA traffic in neurons. Bassell andÂ pharmacologist Yue Feng recently received a grant from the National Institute of Child Health and Development to study FMRP’s regulation of RNA in greater detail. The grant was one of several at Emory funded through the American Recovery and Reinvestment Act’s support for the NIH.
In the video interview above, Bassell explains his work on microRNAs in neurons. Below is a microscope image, provided by Bassell, showing the pattern of FMRP’s localization in neurons.