Our Research
The main research focus of the Hagerman laboratory is on the pathogenic mechanisms that cause fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). Although both fragile X syndrome and FXTAS are caused by CGG-repeat expansions in the fragile X mental retardation 1 (FMR1) gene, the two disorders affect different groups of individuals and operate through entirely different molecular genetic mechanisms. Understanding the alterations of FMR1 gene expression that lead to these two separate disorders, and the development of targeted therapies for both fragile X syndrome and FXTAS, are the fundamental objectives of the lab.
Fragile X-associated tremor/ataxia syndrome (FXTAS) – Since our discovery of this neurodegenerative disorder in 2001, we have been involved with its characterization at the molecular, cellular, neuropathologic, and clinical levels. Based on our parallel discovery of elevated FMR1 mRNA in carriers of premutation alleles (55-200 CGG repeats), we and others have proposed that the pathogenesis of FXTAS involves “RNA toxicity” of the mRNA, by virtue of sequestration of one or more RNA binding proteins by the expanded CGG-repeat RNA.
At present, research in our lab involves both human and mouse models to elucidate additional features of the neuropathology:
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To further investigate the RNA toxicity/sequestration mechanisms thought to underlie FXTAS
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To develop targeted treatments for FXTAS, based on discoveries related to disease mechanism
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To further characterize the mitochondrial dysfunction that is likely to play a central role in disease pathogenesis.
Fragile X syndrome – Our main effort is directed toward the development of targeted approaches for induction of FMRP expression in individuals with premutation or full mutation alleles of the FMR1 gene, who are producing low levels of the FMR1 protein (FMRP).
Although much of this work is still in progress, strategies generally include disruption of CGG-repeat secondary structure, and developing methods to block the effects of microRNA regulation of the FMR1 gene at the level of translation.
Fragile X-associated disorders – We are developing methods for characterizing the precise size of the CGG-repeat region, using the method of SMRT sequencing developed by Pacific Biosciences. Our objective is to be able to sequence genomic DNA directly, without the need for either PCR-based methods or bisulfite treatment, for assessment of methylation status.
We are also interested in developing high-throughput methods for population screening for expanded FMR1 alleles.
Finally, we are implementing more quantitative methods for assessing FMRP levels in blood and other tissues.
Hagerman Publications on PubMed
PJ Hagerman publications - All
PJ Hagerman publications on FXTAS
PJ Hagerman publications on FXS