FRAXA Grant to Alan Tartakoff, PhD — Case Western Reserve University

FRAXA Awards:

$63,000 in 2000
$30,000 in 1999
$30,000 in 1998


Transport of the Fragile X Protein:

Generation of monoclonal antibodies to FMRP, FXR1 and FXR2

by Alan Tartakoff, 7/1/2000

My cell biology research laboratory is focused on three aspects of the biology of FMRP, the protein which is missing in the Fragile X Syndrome.

1. Independent of the functions of FMRP, we have taken the first steps toward developing a protein-therapeutic strategy for the Fragile X Syndrome. This intiative stems from recent success in delivering other proteins into the cytoplasm and nucleus of cells, both when working with cells in culture and in experiments with mice. For example, when appropriately modified forms of proteins are injected into the peritoneal cavity of mice, they arrive – within hours – inside cells throughout the body, including many nerve cells of the brain. In order for such delivery to occur, the protein in question must be equipped with a “tag” which causes its uptake. Our present efforts are directed at adapting this novel technology for delivery of FMRP and learning how to design a tag which ultimately will be removed, so that altogether normal FMRP will be present in the recipient cells.

2. FMRP has many of the structural characteristics of proteins which shuttle between the nucleus and cytoplasm of cells and – in doing so – participate in the export of mRNAs which then direct protein synthesis in the cytoplasm. In order to learn whether export of mRNA is among the functions of FMRP, we are attempting to learn how and when FMRP does travel between the nucleus and cytoplasm. This area of investigation is controversial and has led to several seemingly contradictory conclusions in the past. We have recently formulated a model – which we are now testing – which reconciles all the disparate observations. If we can understand how and why FMRP visits the nucleus, we will be well-situated to understand its functions.

3. The field of Fragile X research has been plagued by an absence of antibodies which cleanly discriminate between FMRP and two closely related proteins. For example, only a single, non-discriminatory antibody is commercially available. We have therefore undertaken the production of a panel of discriminatory antibodies which will be made public. They should be valuable both for diagnosis and for investigation of the fundamental biology of the Fragile X Syndrome.