Navigation Links
Angelman syndrome deficits rescued in mice

Children with Angelman syndrome are often seen laughing and smiling, but this cheerful demeanor masks serious neurological problems ?mental retardation, movement problems and seizures.

ew research in mice, however, suggests that many of these deficits could be alleviated.

Edwin Weeber, Ph.D., and colleagues reversed the neurological deficits in a mouse model of Angelman syndrome by preventing the inhibition of CaMKII, an enzyme highly expressed in brain regions affected by Angelman syndrome.

The results, which appear in the March issue of Nature Neuroscience (currently available online), reveal an important part of the mechanism underlying the condition and point to potential therapeutic targets for treating these symptoms.

Angelman syndrome, which affects approximately one in 15,000 children, is a debilitating neurological disorder characterized by mental retardation, severely limited speech, and movement and balance problems.

In 1997, researchers determined that Angelman syndrome was caused by a mutation in a single gene, called UBE3A. They subsequently developed a mouse model of Angelman syndrome by mutating this gene.

But the finding was baffling, said Weeber, because UBE3A is a "housekeeping" gene, meaning that it broadly regulates cellular processes not particularly specific for any of the neurological deficits seen in these children. Specifically, the protein encoded by UBE3A "tags" other proteins for degradation by the cellular "garbage disposal," the proteasome.

"The most difficult thing to rationalize was that this housekeeping gene ?which nobody thought did anything ?caused severe mental retardation," said Weeber, an assistant professor of Molecular Physiology and Biophysics and Pharmacology and senior author on the study.

"So we started trying to identify some of the protein's molecular targets."

In the process, Weeber and colleagues identified an abnormality i n the Angelman syndrome mouse model ?changes in an enzyme called calcium/calmodulin-dependent protein kinase II (CaMKII), which is important in the cellular processes that underlie learning and memory.

They found that, in Angelman syndrome, CaMKII activity was reduced due to an inhibitory chemical modification (phosphorylation). Because of CaMKII's prominent role in neuronal function, Weeber suspected that this might account for many of the neurological deficits seen in Angelman syndrome children.

Fortuitously, one of Weeber's colleagues ?Ype Elgersma, Ph.D., at Erasmus Medical Center in Rotterdam, Netherlands ?had created a mouse with a mutation that prevented this inhibition of CaMKII.

The researchers decided to breed the Angelman mice with the CaMKII mutant mice to see if counteracting the CaMKII inhibition would alleviate the neurological problems.

The researchers then ran the resulting "double mutants" through a battery of neurological and cognitive tests.

Angelman mice performed poorly on learning and memory tasks and displayed impaired motor coordination.

The double mutants, however, showed normal learning and memory and motor coordination. And while the Angelman mice were also prone to seizures, the double mutants showed very low seizure susceptibility.

Weeber was surprised by the robust results. "We thought we might rescue some of the deficits that we saw in the mouse model," he said. "We had no idea that we were going to rescue basically everything."

Although impossible to apply the genetic engineering used in the current study to correct these deficits in mice to humans, Weeber thinks that the findings may point to new therapeutic targets for the disorder.

"It's very conceivable that if we can figure out what lies between UBE3A and CaMKII ?and if it's a specific path ?then that could be a therapeutic target."

But the results may apply more broadly, Weeber s aid, to other types of mental retardation syndromes that remained unexplained and untreatable.

"There are a lot of mental retardation syndromes that we still don't understand. Maybe the changes in CaMKII associated with Angelman syndrome could be implicated in other mental retardation syndromes as well."


Source:Vanderbilt University Medical Center

Related biology news :

1. 15-year hunt finds cause of pseudothalidomide syndrome
2. Gene for immune deficiency syndromes found
3. Removing DNA repair gene causes metabolic syndrome
4. Congenital rubella syndrome nearly eradicated in the US
5. Researchers link two more genes to sudden infant death syndrome
6. Down syndrome: Its not just the age factor
7. A potential biological cause for sudden infant death syndrome
8. Drug treatment improves learning in mice with Down syndrome symptoms, Stanford/Packard study shows
9. Chronic fatigue syndrome impairs a persons slow wave activity during sleep
10. Experimental drug reverses key cognitive deficits, pathology in Alzheimers
11. Mayo Clinic study suggests that a central nervous system viral infection can lead to memory deficits
Post Your Comments:

(Date:11/9/2015)...  Synaptics Inc. (NASDAQ: SYNA ), the leading ... into the automotive market with a comprehensive and dedicated ... consumer electronics human interface innovation. Synaptics, industry-leading touch controllers, ... automotive industry and will be implemented in numerous locations ... , Japan , and ...
(Date:10/29/2015)... 29, 2015  The J. Craig Venter Institute (JCVI) ... Synthesis and Biosecurity: Lessons Learned and Options for the ... and Human Services guidance for synthetic biology providers has ... --> --> Synthetic biology ... potential to pose unique biosecurity threats. It now is ...
(Date:10/29/2015)... NXTD ) ("NXT-ID" or ... the growing mobile commerce market and creator of ... leading marketplace to discover and buy innovative technology ... on StackSocial for this holiday season.   ... a biometric authentication company focused on the growing ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... Halozyme Therapeutics, Inc. (NASDAQ: HALO ) will be ... York on Wednesday, December 2 at 9:30 a.m. ET/6:30 ... CEO, will provide a corporate overview. th Annual ... 1:00 p.m. ET/10:00 a.m. PT . Jim Mazzola , ... corporate overview. --> th Annual Oppenheimer Healthcare Conference ...
(Date:11/24/2015)... ... November 24, 2015 , ... Copper is an essential ... bound to proteins, copper is also toxic to cells. With a $1.3 million ... (WPI) will conduct a systematic study of copper in the bacteria Pseudomonas aeruginosa ...
(Date:11/24/2015)... Nov. 24, 2015 /PRNewswire/ - Aeterna Zentaris Inc. (NASDAQ: ... on behalf of the Toronto Stock Exchange, confirms that ... are no corporate developments that would cause the recent ... --> --> About Aeterna Zentaris Inc. ... --> Aeterna Zentaris is a specialty biopharmaceutical ...
(Date:11/24/2015)... , November 24, 2015 ... market research report "Oligonucleotide Synthesis Market by Product & ... Gene Synthesis, Diagnostic, DNA, RNAi), End-User (Research, Pharmaceutical & ... by MarketsandMarkets, the market is expected to reach USD ... 2015, at a CAGR of 10.1% during the forecast ...
Breaking Biology Technology: