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Fragilex Canada Foundation

What is Fragile X ?

The term Fragile X refers to a group of conditions due to defects in a gene on the X chromosome:

  • Fragile X syndrome (FXS)
  • Fragile X-associated Tremor Ataxia Syndrome (FXTAS)
  • Fragile X-associated primary ovarian insufficiency (FXPOI)

Fragile X syndrome (FXS), first known as Martin-Bell syndrome, is the most common inherited form of mental impairment. FXS affects 1 in 4,000 boys and 1 in 6,000 girls of all races and ethnic groups. While Fragile X individuals have a normal life expectancy, most will need support and care for their entire lives.

A single gene in the brain cells shuts down, causing Fragile X syndrome. In 1991, scientists discovered the defect in a gene on the X chromosome (called FMR1) that causes FXS. In affected individuals, this gene is shut down and cannot manufacture the protein it normally makes – a protein vital for normal brain development and functioning.

Large-scale population studies of Fragile X still need to be done, but it is clear that this is one of the most common genetic diseases in humans. Most people with Fragile X are not yet correctly diagnosed.

Research is aimed at developing effective treatments. In addition, this research is leading to better understanding and treatments for other conditions, such as autism, and Alzheimer’s Disease.

Grant reports

FXRFC Awards Three Research Grants for 2011

The Fragile X Research Foundation of Canada continues its drive to increase the number of scientists working towards finding a treatment for Fragile X. The FXRFC is currently funding six research projects across Canada, and has recently awarded three additional grants to start in 2011, committing another $105,000 for research aimed at finding a treatment or cure for Fragile X. The new projects at the University of Victoria, McMaster University, and the University of Toronto will yield valuable information on the pathology of Fragile X, and should stimulate further research in this area.

Our approach to research funding has always been to be flexible in order to maximize our ability to identify new “therapeutic targets” that can guide the development of future treatments.In the previous edition of this Newsletter, we reported on the development of a new class of drug as a possible treatment for Fragile X. The development of this drug is based on the “mGluR Theory” of Fragile X, a well validated therapeutic target. 
Because clinical drug trials using mGluR5 blockers are well underway at the Fragile X Clinic at Surrey Place Centre in Toronto, the FXRFC is now focusing on identifying new and different therapeutic targets for the treatment of Fragile X.

Below are brief descriptions of these new projects, as presented for you by the researchers. If you would like to explore the entire portfolio of FXRFC funded research, past and present, please click on the archives to the right.

Scientists are making significant progress in understanding Fragile X syndrome and it is a direct result of the work funded with your generous donations – please keep them coming!


Principal Investigator: Dr. Brian  R. Christie Ph.D.
Division of Medical Sciences,  University of Victoria, Island Medical Program  University of British Columbia, Victoria, BC
Postdoctoral Fellow: Dr. Mariana Vetrici, Ph.D.
Amount: $42,500 for a period of 1 year
Start Date: April 1, 2011

FMRP expression in Dentate Gyrus mediates neurogenesis, NMDA receptor expression and function, anxiety and context discrimination

ragile X Syndrome (FXS) is the most common form of inherited intellectual disability. The disorder is caused by loss of function of a single gene on the X chromosome, the Fragile-X mental retardation gene-1 (Fmr1) and subse-quently the protein FMRP (Fragile X mental retardation protein) is not produced. We are in the process of developing some exciting new mouse models to investigate the role of FMRP in synaptic physiology. Thus far, considerable emphasis has been placed on studying the role of metabotropic glutamate receptors (mGluR) in FXS, however we have recently presented significant evidence that a different protein, the n-methyl-D-aspartate (NMDA) receptors may be more profoundly affected in some brain regions, like the hippocampus.

The hippocampus is a brain region linked to memory, social and learning behaviours. Production of FMRP is normally high in the hippocampus, particularly in the dentate gyrus (DG) and CA1 subfields. This suggests that loss of Fmr1 may significantly impact hippocampal functioning. Surprisingly, most forms of synaptic plasticity, as well as learning behaviours that require a normally functioning CA1 subregion of the brain are not impaired in adult Fmr1 KO (Knock Out) mice. The CA1 subfield has been shown to exhibit enhanced mGluR mediated long-term depression (LTD), which tends to weaken neuronal connections. However the behavioural significance of this form of LTD has proven to be elusive to date. Our research indicates that deficits in NMDA recep-tors can profoundly impact certain forms of social behaviour and learning that require the dentate gyrus, and provides insight into new therapeutic targets for this devastating disorder.

Principal Investigator: Dr. Min Zhuo Ph.D.
Department of Physiology, University of Toronto
Postdoctoral Fellow: Dr. Kohei Koga Ph.D.
Amount: $42,500 for a period of 1 year
Start Date: April 1, 2011

The rescue of FMRP- related learning and memory deficit

Fragile X syndrome, the most commonly inherited form of intellectual disability and the most common cause of autism, is caused by the loss of the Fragile X mental retardation protein (FMRP) encoded by the Fragile X mental retardation 1 (Fmr1) gene. The loss of Fmr1 is characterized by cognitive impairment, and deficits of learning and memory. At the synaptic and cellular levels, the absence of Fmr1 may lead to the loss of learning-related forms of synaptic plasticity. This leads to decreased Long Term Potentiation (LTP), and increased Long Term Depression (LTD), both of which cause weakening of the connections between neurons. Using the genetic mouse model of Fragile X (Fmr1 KO), we have reported that FMRP is important for LTP in the prefrontal cortex of the brain including the anterior cingulate cortex (ACC) and behavioral trace fear memory.  Since NMDA NR2B receptors also play important roles in learning  related LTP in the hippocampus and ACC, it is conceivable that enhancing NMDA NR2B receptor functions may reverse some of memory-defects in Fragile X patients. Recently, Dr. Liu’s laboratory reported that treatment with magnesium-L-threonate (MgT) leads to the enhancement of learning and working memory. At the synaptic level, NMDA NR2B protein and receptor function are significantly enhanced in the hippocampus of the brain. In addition, presynaptic functions of glutamate synapses are also enhanced. We thus hypothesize  that MgT may be used to ‘treat’ abnormal synaptic plasticity observed in Fmr1 KO mice, and may reverse the learning and memory impairments of these mice.

To test this hypothesis, we will system-atically attempt to reverse FMRP-related learning and memory deficit behavior, and learning-related LTP at the synaptic level in the ACC of Fmr1 KO mice. Integrative neurobiological approaches including electrophysiological and biochemical methods will be used. This project will provide the proof of the concept evidence that MgT may serve as a possible novel treatment for patients with Fragile X Syndrome.

Principal Investigator: Dr. Laurie Doering, Ph.D.
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario
Amount: $15,235 for a period of 1 year
Start Date: May 1, 2011

Identification of Molecular Events in Fragile X Synaptogenesis

Glial cells are essential players in all aspects of brain development, function and disease. Astrocytes, a type of glial cell, are critical for the proper formation, growth and maintenance of neurons and synaptic connections in the nervous system. In virtually all disorders of the brain, astrocytes contribute to the altered function or pathology. Astrocytes are also intimately involved in neurodevel-opmental disorders such as Rett syndrome. To date, the role of astrocytes in the genesis of Fragile X Syndrome has not been studied in depth.

The experiments that we will conduct in our lab will strengthen our understanding of how astrocytes contribute to the abnormal synaptogenesis that characterizes Fragile X. At the basic research level, this proposal focuses on understanding the roles of astrocytes during the early developmental periods in the brain that center on the maturation of neuronal dendrites, spines and synapses. From a clinical perspective, the experiments will provide new insight and potentially open new directions to intervene early in children with Fragile X by the administration of drugs that influence astrocyte and neuronal signaling.