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Fragile X syndrome is the most common cause of autism. Even though the single gene that’s responsible for it was discovered in 1991, and the disease is detected by a simple blood test, there’s no treatment or cure.

A team of researchers led by Michigan State University, however, has provided a promising lead in battling this disease. In the current issue of Nature Communications, the scientists identified a single protein that appears to be the culprit in causing many behavioral symptoms as well as molecular and cellular abnormalities related to Fragile X.

“We began with 600-800 potential protein targets, searching for the equivalent of a needle in a haystack,” said Hongbing Wang, MSU physiologist and study co-author. “Our needle turned out to be ADCY1. When we compared levels of this protein in Fragile X mouse model to normal controls, we saw a 20-25 percent increase of ADCY1.”

Subsequent tests of the team’s prime-target protein on the Fragile X mouse model revealed four key results. First, by reducing the expression of ADCY1, the team eliminated many autism-like behaviors. Second, the protein’s increased expression caused increased signaling in neurons. By reducing levels of ADCY1, the team dampened neuron signaling to levels within a normal range.

 

Source: Researchers find promising lead that reduces autism symptoms and more – Medical News Today


Research into autism as a symptom of other genetic disorders sheds some light on the molecular mechanisms behind the pervasive and elusive condition.

Source: Searching for genetic links between autism and other disorders – Medical News Today


Original post from Medical News Today

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By identifying a key signaling defect within a specific membrane structure in all cells, University of California, Irvine researchers believe, they have found both a possible reliable biomarker for diagnosing certain forms of autism and a potential therapeutic target.

Dr. J. Jay Gargus, Ian Parker and colleagues at the UCI Center for Autism Research & Translation examined skin biopsies of patients with three very different genetic types of the disorder (fragile X syndrome and tuberous sclerosis 1 and 2). They discovered that a cellular calcium signaling process involving the inositol trisphosphate receptor was very much altered.

This IP3R functional defect was located in the endoplasmic reticulum, which is among the specialized membrane compartments in cells called organelles, and may underpin cognitive impairments – and possibly digestive and immune problems – associated with autism.

“We believe this finding will be another arrow in the quiver for early and accurate diagnoses of autism spectrum disorders,” said Gargus, director of the Center for Autism Research & Translation and professor of pediatrics and physiology & biophysics. “Equally exciting, it also presents a target of a molecular class already well-established to be useful for drug discovery.”

Study results appear online in Translational Psychiatry, a Nature publication, “Shared functional defect in IP3R-mediated calcium signaling in diverse monogenic autism syndromes” doi:10.1038/tp.2015.123 (open access).

Autism spectrum disorder is a range of complex neurodevelopmental disorders affecting 2 percent of U.S. children. The social and economic burden of ASD is enormous, currently estimated at more than $66 billion per year in the U.S. alone. Drug development has proven problematic due to the limited understanding of the underlying causes of ASD, as demonstrated by the recent failure of several much anticipated drug trials.

There are also no current, reliable diagnostic biomarkers for ASD. Genetic research has identified hundreds of genes that are involved, which impedes diagnosis and, ultimately, drug development. There simply may be too many targets, each with too small an effect.

Many of these genes associated with ASD, however, have been found to be part of the same signaling pathway, and multiple defects in this pathway may converge to produce a large functional change.

The UCI scientists detected such a convergence in the IP3R calcium channel in an organelle called the endoplasmic reticulum. Organelles are membrane structures within cells with specialized cellular functions. According to Gargus, diseases of the organelles, such as the ER, are an emerging field in medicine, with several well-recognized neurological ailments linked to two other ones, the mitochondria and lysosomes.

The IP3R controls the release of calcium from the ER. In the brain, calcium is used to communicate information within and between neurons, and it activates a host of other cell functions, including ones regulating learning and memory, neuronal excitability and neurotransmitter release – areas known to be dysfunctional in ASD.

“We propose that the proper function of this channel and its signaling pathway is critical for normal performance of neurons and that this signaling pathway represents a key ‘hub’ in the pathogenesis of ASD,” said Parker, a fellow of London’s Royal Society and UCI professor of neurobiology & behavior, who studies cellular calcium signaling.

To see if IP3R function is altered across the autism spectrum, clinical researchers at the Center for Autism & Neurodevelopmental Disorders – which is affiliated with the Center for Autism Research & Translation – are currently expanding the study and have begun to examine children with and without typical ASD for the same signaling abnormalities. These patients undergo complete behavioral diagnostic testing, and sophisticated EEG, sleep and biochemical studies are performed. This includes the sequencing of their entire genome. Also, skin cell samples are cultured and made available to lab-based researchers for functional assays.

In the area of drug discovery, scientists at the Center for Autism Research & Translation continue to probe the IP3R channel, specifically how it regulates the level of neuron excitability. The brains of people who have autism show signs of hyperexcitability, which is also seen in epilepsy, a disorder increasingly found to be associated with ASD. Cells from individuals who have autism exhibit depressed levels of calcium signaling, and this might explain why these patients experience this hyperexcitability. By restoring the release of calcium from the IP3R, the researchers believe, they can apply a “brake” on this activity.

Adapted by MNT from original media release

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References

 

Galina Schmunk, Bryan Boubion and Ian Smith of UCI contributed to the study, which received support from the National Institutes of Health (grants GM048071 and GM1000201) and the William & Nancy Thompson Family Foundation. The discovery is being patented by the University of California as a diagnostic tool and for identifying potential therapeutic agents.

University of California – Irvine  …………………’


Original post from Medical News Today

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Fragile X syndrome is the most common inherited intellectual disability and the greatest single genetic contributor to autism. Unlocking the mechanisms behind fragile X could make important revelations about the brain.

In a new study published June 4 in the journal Cell Reports, researchers from the University of Wisconsin-Madison Waisman Center and Department of Neuroscience show that two proteins implicated in fragile X play a crucial role in the proper development of neurons in mice. They also show that while the two proteins act through distinct mechanisms in the formation of new neurons — which send, receive and process information in the brain — they also share some duties.

‘This is the first demonstration of the additive function of fragile X proteins in neuronal development,’ says study corresponding author and Waisman Center and Department of Neuroscience Professor Xinyu Zhao.

Relatively little is known about the underlying mechanisms that lead to the cognitive and learning deficits in fragile X syndrome, Zhao says, making it difficult to devise effective therapies. She studies the two fragile X proteins, FMRP and FXR2P, because doing so could yield new information that ultimately leads to treatment for fragile X and other disorders marked by defects in neuronal development, like autism and schizophrenia.

For instance, while FXR2P has been shown to be important in autism, the function of the protein and its contribution to fragile X syndrome has been unclear, Zhao says.

Fragile X is a genetic condition that affects one in 4,000 males and one in 8,000 females. It’s linked to a mutation in the gene that makes the FMRP protein, located on the X chromosome. Up to a third of people with fragile X also have autism.

Children with the syndrome are more prone to attention deficit disorder and a diagnosis on the autism spectrum; display physical features such as flat feet, a prominent jaw and forehead, and a long and narrow face, and may have anxiety.

Additionally, an estimated one in 250 women and one in 500 men carry a ‘premutation’ on the gene that makes FMRP protein, which renders the gene unstable. Carriers can pass it on to future generations and are at greater risk for a Parkinson’s disease-like disorder called fragile X-associated tremor/ataxia syndrome. They may also be more prone to stress and other challenges.

In a previous study, Zhao’s team showed that both FMRP and FXR2P are integral for new neuron production in adult mice and are important for learning and cognition. In the current study, the research team looked at the function of the proteins in the maturation of newly formed adult neurons.

The researchers found that mice lacking the FXR2P protein had impaired performance in learning and memory tasks. Using techniques to study newly formed neurons in the brain, the team also found these mice had neurons that did not mature properly. The neurons were also less well connected to other neurons that form important circuits in the brain compared to mice with the protein.

The team also highlighted a new interaction between the FXR2P protein and a specific neuronal receptor, a protein charged with receiving messages and passing along information, and showed that the two work together for proper neuronal development. Additionally, it revealed that FXR2P and FMRP work together in regulating this receptor’s activity and the maturation of neurons.

‘The findings suggest that fostering new nerve cell development during the postnatal period may have therapeutic potential for people with fragile X syndrome and other neurological disorders,’ says Zhao.

Her research group will continue to study these proteins and the role they play in neural development and fragile X syndrome — work that’s likely to influence other fields of inquiry in autism and beyond. The lab will also work toward translating the findings in mice into human therapies. It is far more challenging to study brain development in people, so mice serve as a model for these studies.

‘If we can find a way to reactivate the FMRP gene, we may be able to treat the disease,’ says Zhao.

Adapted by MNT from original media release

References

 

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