ICAM5 Protein May Be Target to Treat Cognitive Impairment in Fragile X, Study Suggests

ICAM5 Protein May Be Target to Treat Cognitive Impairment in Fragile X, Study Suggests
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Reducing the level of a protein called ICAM5 in the brain improved memory and eased anxiety in a mouse model of fragile X syndrome, a new study shows.

The study, “ICAM5 as a novel target for treating cognitive impairment in Fragile X Syndrome,” was published in the Journal of Neuroscience.

Fragile X, the most common genetic cause of autism and intellectual disability, results from a mutation in the FMR1 gene that leads to no production of the fragile X mental retardation protein (FMRP). That loss of FMRP impairs the expression of other genes.

The disorder also is associated with abnormal formation of dendritic spines, which are tiny protrusions of nerve cells with an essential role in the synapse (the site where neurons communicate). Under normal conditions, FMRP levels are high in dendritic spines, where the protein regulates RNA localization and protein transport, among other processes.

But in fragile X, the absence of FMRP results in excessive protein production and other defects in dendritic spines.

ICAM5, a protein that regulates dendritic spine maturation and cognitive function, has been suggested as one of the targets of FMRP. Still, the role of ICAM5 in fragile X remains unclear.

Researchers in China addressed this topic in a mouse model of fragile X. They examined the messenger RNA (mRNA) of ICAM5 during brain development. Of note, mRNA is produced from DNA in protein production.

Results indicated that lack of Fmr1 in these mice was associated with excessive mRNA levels of ICAM5 during late brain development. The lower the levels of FMRP, the higher those of the mRNA of ICAM5 and the greater the extent of structural abnormalities in dendritic spines.

The team then assessed the effect of reducing ICAM5 levels in nerve cells lacking Fmr1. Results revealed that lowering protein levels led to correction of spine abnormalities in vitro (in a lab dish).

Also, reducing ICAM5 levels in the dentate gyrus — an area of the brain that is key in memory and adapting to new environments — led to improved memory and eased anxiety-like behaviors in mice with fragile X.

Biochemical analysis further demonstrated that FMRP regulates ICAM5 by binding directly to its mRNA.

Overall, the results suggest that loss of FMRP leads to high ICAM5 levels, dendritic spine abnormalities, and cognitive deficits in fragile X.

“Taken together, our study suggests that ICAM5 is one of the targets of FMRP and implicates [it] in the molecular pathogenesis [development] of FXS [fragile X syndrome],” the researchers wrote.

“ICAM5 could be a therapeutic target for treating cognitive impairment in FXS,” they said.

Iqra holds a MSc in Cellular and Molecular Medicine from the University of Ottawa in Ottawa, Canada. She also holds a BSc in Life Sciences from Queen’s University in Kingston, Canada. Currently, she is completing a PhD in Laboratory Medicine and Pathobiology from the University of Toronto in Toronto, Canada. Her research has ranged from across various disease areas including Alzheimer’s disease, myelodysplastic syndrome, bleeding disorders and rare pediatric brain tumors.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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Iqra holds a MSc in Cellular and Molecular Medicine from the University of Ottawa in Ottawa, Canada. She also holds a BSc in Life Sciences from Queen’s University in Kingston, Canada. Currently, she is completing a PhD in Laboratory Medicine and Pathobiology from the University of Toronto in Toronto, Canada. Her research has ranged from across various disease areas including Alzheimer’s disease, myelodysplastic syndrome, bleeding disorders and rare pediatric brain tumors.
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