Paul Hagerman

Paul Hagerman's picture
Professor

MD, PhD

(530) 754-7266; (530) 754-7270 - Lisa, Exec Asst
pjhagerman@ucdavis.edu

HagermanPJ_NIHbio_050310_general.pdf
Lab Webpage: 
http://wizard1.ucdavis.edu/


Research Interests

The principal objective of the Hagerman laboratory is a greater understanding of the molecular underpinnings of the fragile X family of disorders, including the neurodevelopmental disorder, fragile X syndrome, and the neurodegenerative disorder, 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.

 

FXTAS represents the most severe form of clinical involvement associated with premutation FMR1 alleles (55-200 CGG repeats); its core features are intention tremor and/or ataxia, with peripheral neuropathy, autonomic dysfunction, and gradual cognitive decline beginning with memory and executive function deficits. Psychiatric features are often present, and may include anxiety, dysinhibition, depression, and apathy. MRI features of FXTAS include global brain atrophy, white matter disease in the subcortical, middle cerebellar peduncles (MCP) and periventricular regions.

Current research on FXTAS

Our laboratory is involved with a broad range of molecular and translational/clinical projects related to FXTAS, and this research effort forms the basis for our NeuroTherapeutics Research Institute (NTRI) consortium effort. The molecular basis of FXTAS appears to be a toxic gain-of-function of the FMR1 mRNA, which contains the expanded CGG repeat; molecular endeavors include:

 

  • Development of oligonucleotide-based approaches to reduce FMR1 RNA in vivo.
  • Defining the timing and reversibility of pathogenic responses to expression of the expanded CGG-repeat RNA.
  • Identification of the initial/early molecular events that couple expression of the expanded CGG-repeat RNA to downstream processes (e.g., cellular stress response, breakdown of nuclear lamin A/C architecture) that are likely to lead to neurodegeneration.
  • Characterization of the components of the intranuclear inclusions and the basis for inclusion formation.
  • Development of approaches for delivery of therapeutic agents across the blood-brain-barrier.
  • Understanding of the detailed molecular mechanisms by which the expanded CGG-repeat RNA triggers the pathogenic response in FXTAS.

 

Fragile X syndrome is the most common inherited form of cognitive impairment, also displaying a broad spectrum of emotional and behavioral involvement. The promoter region of full mutation forms of the FMR1 gene (> 200 CGG repeats) is generally hypermethylated and transcriptionally silent, resulting in little or no FMR1 mRNA protein (FMRP). FMRP is an mRNA transport protein and a negative regulator of translation for messages that are utilized in synaptic plasticity. Thus, fragile X syndrome is intrinsically a protein-deficiency syndrome. Fragile X syndrome is also an important genetic basis of autism, with over 50% of boys with fragile X syndrome demonstrating features of autism or autism spectrum disorders. Moreover, approximately 2 to 6% of children with autism have fragile X syndrome. The phenotype of fragile X syndrome includes hyperactivity, attention problems, anxiety, sensory integration problems leading to tactile defensiveness, unusual hand mannerisms such as hand flapping, shyness, and poor eye contact.

Current research on fragile X syndrome

The focus of our current molecular research is the regulation of expression of the gene at the transcriptional and translational levels, since reduced FMRP levels arise through both transcriptional silencing and reduced efficiency of translation of the expanded CGG-repeat mRNA. Our work in this area includes:

 

  • Identification of sequence elements within the FMR1 5'UTR that contribute to increased transcriptional activity with increasing CGG-repeat length. Attenuation of this increase is a potential approach to targeted therapies for FXTAS.
  • Studies of the mechanism by which translation is impaired by the expanded CGG repeat in RNA. Improved translation from expanded-repeat mRNA would, in principle, supply more protein in cases of fragile X syndrome.
  • Further definition of the relationship between epigenetic modifications and transcriptional activity of FMR1 alleles with full mutation expanded CGG repeats.

 

 

Selected Publications: 

Representative Publications (past two years)
2009

Adams PE, Adams JS, Nguyen DV, Hessl D, Brunberg JA, Tassone F, Zhang W, Koldewyn K, Rivera SM, Grigsby J, Zhang L, Decarli C, Hagerman PJ, Hagerman RJ (2009) Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers. Am J Med Genet B Neuropsychiatr Genet 153B:775-785

Bourgeois JA, Coffey SM, Rivera SM, Hessl D, Gane LW, Tassone F, Greco C, Finucane B, Nelson L, Berry-Kravis E, Grigsby J, Hagerman PJ, Hagerman RJ (2009) A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry 70:852-862

Dodds ED, Tassone F, Hagerman PJ, Lebrilla CB (2009) Polymerase chain reaction, nuclease digestion, and mass spectrometry based assay for the trinucleotide repeat status of the fragile X mental retardation 1 gene. Anal Chem 81:5533-5540

Fernandez-Carvajal I, Walichiewicz P, Xiaosen X, Pan R, Hagerman PJ, Tassone F (2009) Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn 11:324-329

Hagerman PJ, Stafstrom CE (2009) Origins of epilepsy in fragile X syndrome. Epilepsy Curr 9:108-112

Iwahashi C, Tassone F, Hagerman RJ, Yasui D, Parrott G, Nguyen D, Mayeur G, Hagerman PJ (2009) A quantitative ELISA assay for the fragile X mental retardation 1 protein. J Mol Diagn 11:281-289

Ludwig AL, Raske C, Tassone F, Garcia-Arocena D, Hershey JW, Hagerman PJ (2009) Translation of the FMR1 mRNA is not influenced by AGG interruptions. Nucleic Acids Res 37:6896-6904. Epub 2009 Sep 6814

Senturk D, Nguyen DV, Tassone F, Hagerman RJ, Carroll RJ, Hagerman PJ (2009) Covariate adjusted correlation analysis with application to FMR1 premutation female carrier data. Biometrics 65:781-792

 

2010

Chen Y, Tassone F, Berman RF, Hagerman PJ, Hagerman RJ, Willemsen R, Pessah IN (2010) Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration. Hum Mol Genet 19:196-208

Garcia-Arocena D, Hagerman PJ (2010) Advances in understanding the molecular basis of FXTAS. Hum Mol Genet 19:R83-89

Garcia-Arocena D, Yang JE, Brouwer JR, Tassone F, Iwahashi C, Berry-Kravis EM, Goetz CG, Sumis AM, Zhou L, Nguyen DV, Campos L, Howell E, Ludwig A, Greco C, Willemsen R, Hagerman RJ, Hagerman PJ (2010) Fibroblast phenotype in male carriers of FMR1 premutation alleles. Hum Mol Genet 19:299-312

Raske C, Hagerman PJ (2009) Molecular pathogenesis of fragile X-associated tremor/ataxia syndrome. J Investig Med 57:825-829

Ross-Inta C, Omanska-Klusek A, Wong S, Barrow C, Garcia-Arocena D, Iwahashi C, Berry-Kravis E, Hagerman R, Hagerman PJ, Giulivi C (2010) Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome. Biochem J :Jun 1. [Epub ahead of print]

Sellier C, Rau F, Liu Y, Tassone F, Hukema RK, Gattoni R, Schneider A, Richard S, Willemsen R, Elliott DJ, Hagerman PJ, Charlet-Berguerand N (2010) Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients. EMBO J 29:1248-1261

Other Affiliations: 
SOM: Department of Biochemistry and Molecular Medicine NeuroTherapeutics Research Institute (NTRI) M.I.N.D. Institute Biochemistry, Molecular, Cellular and Developmental Biology Graduate Group Genetics Graduate Group
Current Students: 
Kasia Koscielska (BMCDB) Erick Loomis (GGG)
Postdocs and Research Personnel: 
Anna Ludwig Susan Hulsizer Sumaira Amir
Staff Members: 
Chris Iwahashi Chris Raske Glenda Espinal Katherine Cheung Lisa Makhoul Kylee Cook

Current Students

Name Phone Email
Kasia Koscielska (BMCDB)
Erick Loomis (GGG)

Postdocs and Research Personnel

Name Current Position Title Phone Email
Anna Ludwig
Susan Hulsizer
Sumaira Amir

Staff Members

Name Title Phone Email
Chris Iwahashi
Chris Raske
Glenda Espinal
Katherine Cheung
Lisa Makhoul
Kylee Cook