Contributions of a 'sorting nexin' protein to learning impairments in Down's syndrome

April 23, 2014
Contributions of a ‘sorting nexin’ protein to learning impairments in Down’s syndrome
The sorting nexin SNX27 (green) is found primarily at dendritic spines, as indicated by overlapping fluorescence with postsynaptic density protein-95 (PSD-95; red). Credit: Ref. 1 / L. S. Loo et al.

Every year, roughly 1 in 1,000 children worldwide are born with Down's syndrome. This developmental disorder, associated with potentially severe intellectual and learning disabilities among other characteristics, is caused by the presence of a third copy of chromosome 21, resulting in abnormal activity levels for the more than 300 genes on this chromosome. Scientists have had difficulty identifying the core genes responsible for the disorder, but Wanjin Hong's team at the A*STAR Institute of Molecular and Cell Biology in Singapore have identified a gene with an important role in brain signaling that is one possible culprit1.

Hong and colleagues focused their attention on sorting nexin 27 (SNX27), one of a family of proteins that coordinate movement of other proteins to different compartments of the cell. Previously, the team showed that SNX27 contains distinctive structural features that suggested it may be active at neuronal synapses2. In addition, mice lacking this displayed severe developmental and neurological abnormalities, including measurable cognitive defects.

"SNX27-knockout mice demonstrated behavioral characteristics that make them good candidates for research on learning and memory," explains Li Shen Loo, a research scientist in Hong's laboratory. Intriguingly, this study also revealed that lower levels of SNX27 were also apparent in from patients with Down's syndrome, and showed that SNX27 production is reduced by one of the genes present on chromosome 212.

Loo and Hong decided to examine brain structure and function in SNX27-deficient mice. They observed considerable fluid accumulation within the mutant mouse brain and underdevelopment of the dentate gyrus—a part of the brain responsible for learning and memory. These alterations made further analysis tricky, according to Loo.

"The knockout brains were too soft and watery to characterize with traditional techniques," she says, "but I was able to investigate the mechanism of memory impairment in these mice using live cell imaging techniques." By examining different combinations of fluorescently-labeled proteins in neurons from wild-type and SNX27-deficient mice, Loo and her colleagues could directly observe the real-time behavior of individual synapses in the presence and absence of SNX27.

Those experiments confirmed that SNX27 is predominantly found within dendritic spines (see image), the part of the neuron that receives incoming signals at the synapse. SNX27 specifically resides within structures called recycling endosomes, which help to shuttle neurotransmitter receptors and other proteins between the cellular interior and the cell surface.

When the researchers experimentally simulated long-term potentiation, the neuronal activation process associated with memory building, they observed that SNX27-bearing endosomes moved from the cell interior to the surface. These endosomes also contained GluA1, a component of the receptor for the neurotransmitter glutamate. In the absence of SNX27, GluA1 is no longer efficiently transported to the surface of the dendritic spines—in fact, it become susceptible to degradation. Since glutamate–GluA1 signaling is critical for long-term potentiation, SNX27 could play a major role in enabling transmission of memory-related signals.

"These results could account for the learning deficits observed in Down's syndrome," notes Loo, who sees a potential therapeutic opportunity. "Since Down's syndrome patients produce less SNX27, re-introducing the protein may restore memory function," she says.

Explore further: Scientists discover protein's role in human memory and learning functions

More information: Loo, L. S., Tang, N., Al-Haddawi, M., Dawe, G. S. & Hong, W. "A role for sorting nexin 27 in AMPA receptor trafficking." Nature Communications 5, 3176 (2014). dx.doi.org/10.1038/ncomms4176

Wang, X., Zhao, Y., Zhang, X., Badie, H., Zhou, Y. et al. "Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome." Nature Medicine 19, 473–480 (2013). dx.doi.org/10.1038/nm.3117

Related Stories

Scientists discover protein's role in human memory and learning functions

February 19, 2014
Scientists at A*STAR's Institute of Molecular and Cell Biology (IMCB) have identified the precise role of the protein, SNX27, in the pathway leading to memory and learning impairment. The study broadens the understanding ...

Researchers unravel molecular roots of Down syndrome

March 24, 2013
Sanford-Burnham researchers discover that the extra chromosome inherited in Down syndrome impairs learning and memory because it leads to low levels of SNX27 protein in the brain.

Further potential insight into the complex neuropathology of Down's syndrome

April 8, 2013
(Medical Xpress)—Researchers at the University of Bristol have revealed new insight into the function of a key protein attributed to impaired learning and memory in Down's syndrome. The findings, published online in Nature ...

Lack of coronin 1 protein causes learning deficits and aggressive behavior

March 26, 2014
Learning and memory relies on the proper processing of signals that stimulate neuronal cells within the brain. Researchers at the Biozentrum of the University of Basel, together with an international team of scientists, has ...

Recommended for you

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Newly discovered gene variants link innate immunity and Alzheimer's disease

July 17, 2017
Three new gene variants, found in a genome wide association study of Alzheimer's disease (AD), point to the brain's immune cells in the onset of the disorder. These genes encode three proteins that are found in microglia, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.