Paul J. Hagerman, M.D., Ph.D.

Professor
4455 Tupper Hall,
Davis Campus
(530) 754-7266
e-mail

Recent/Current
Research Funding

National Institutes of Health

National Institute of Aging

National Institute of Neurological Disorders and Stroke

National Institute of Child Health and Development

NIH Roadmap Initiative (NIDCR)

NIH ARRA

National Ataxia Foundation

National Fragile X Foundation

Private donors

Graduate Group Affiliations

Biochemistry, Molecular, Cellular
and Developmental Biology

Cell and
Developmental Biology

Research Interests

The principal objective of the Hagerman laboratory is a greater understanding of the molecular basis of clinical involvement in fragile X syndrome and autism, with the goal of developing effective therapies for those neurodevelopmental disorders. We are also investigating a newly discovered neurodegenerative disorder, FXTAS, associated with the fragile X gene. Our efforts combine clinical and basic molecular research, the latter involving studies of gene expression at the level of transcription and translation.

For more information, visit the Hagerman Laboratory website

Fragile X Syndrome

Fragile X syndrome is the leading inherited form of mental impairment, affecting about one person in 3,000 worldwide. This disorder is caused by large expansions of a three-base (CGG) repeat within the fragile X gene. For expansions of more than about 200 repeats (full mutation range), the gene generally becomes silent. In the absence of the protein product, FMRP, brain development is impaired. The laboratory is pursuing the development of new approaches for treating fragile X syndrome. We believe that small molecules, including modified DNA and RNA species, that can be targeted to the fragile X gene or its message will prove to be effective agents for the treatment of fragile X. Current areas of research address the following questions regarding expression of the fragile X gene: Why does the fragile X gene remain active in some individuals with fragile X syndrome, even though such individuals possess little or no FMRP? What are the signals that tell the gene to shut down, and can these "silencing" signals be blocked or reversed? Why does the fragile X gene produce as much as ten times more message than normal in some individuals, while protein levels remain below normal? What are the signals that tell the gene to produce higher-than-normal levels of message? What does the protein product of the fragile X gene (FMRP) do? Why is FMRP production reduced even though message levels are high?

FXTAS and the Fragile X Gene

We have recently identified a new neurological disorder in adult carriers of small CGG expansions (55 to 200 repeats; premutation range) who are over 50 years of age. This disorder, called Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), includes progressive action tremor, ataxia and cognitive decline, and has associated findings of neuropathy and emotional disturbances. We estimate that more than 25 percent of all carriers could be affected with this progressive disorder. FXTAS appears to be distinct from fragile X syndrome, although it is associated with the FMR1 gene.
Current areas of research on FXTAS are aimed at the following questions:

• What is the basis for the progressive clinical findings, since FMRP levels are generally within or close to the normal range?
• Could this syndrome be due to overexpression of the fragile X gene message, which is high in these individuals?
• Why don´t all carriers have this disorder? Are other genes involved as well?

Autism

Autism is an increasingly common behavioral disorder consisting of substantially reduced social interactions, impaired or absent language development, and patterned, repetitive behaviors. However, the causes of autism remain obscure. Our laboratory is part of an NIH-funded Center that is investigating the underlying causes, both genetic and environmental, of autism and autism spectrum disorders. The experimental approaches are varied, and will include expression profiling (microarray) analysis and various proteomics methodologies. Our short-term objective is the identification of "biomarkers" that could be used to predict which neonates will go on to develop autism (and which could be prevented from such progression). Our long-term goal is the development of specific therapeutic approaches for the treatment of autism.

Computational Issues

There are several computational problems that will continue to receive attention in our laboratory. Such problems include the development of better tools for the global analysis of microarray and proteomics data.

 

Representative Publications

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 2009. 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 2009. 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 2009. 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. 2009. J Mol Diagn 11:324-329.

Hagerman PJ, Stafstrom CE (2009) Origins of epilepsy in fragile X syndrome. 2009. 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 2009. 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 2009. 65:781-792.

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 2010. 19:196-208.

Garcia-Arocena D, Hagerman PJ (2010) Advances in understanding the molecular basis of FXTAS. Hum Mol Genet 2010. 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 2010. 19:299-312.

Raske C, Hagerman PJ (2009) Molecular pathogenesis of fragile X-associated tremor/ataxia syndrome. J Investig Med 2010. 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 2010. 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. 2010. EMBO J 29:1248-126.

 

Recent/Current Teaching

Upper division courses

• 192 Internship in Biological Chemistry
• 199 Special Study for Advanced Undergraduates

Graduate courses

• 209 Prostaglandins/Leukotrienes and Related Lipids (offered even years)
• 214 Molecular Medicine
• 217 Molecular Genetics of Fungi (odd years)
• 222 Mechanisms of Translational Control (even years)
• 230 Practical NMR
• 231 Biomedical NMR (same as BPH 231)
• 291 Human Genetics Seminar
• 298 Group Study
• 299 Research

Professional courses for medical students

• 410A Molecular and Cell Biology
• 499 Research

 

Honors and Awards

• William Rosen Research Award 2002, National Fragile X Foundation
• Stallone Fund for Autism Research
• UC Davis School of Medicine, Kaiser Award for Excellence In Teaching Basic Sciences
• Milheim Foundation Award for Cancer Research
• Leukemia Society of America Special Fellowship
• Leukemia Society of American Fellowship