University Home | Hospital | Pulse Employment | Contact Us | Search | News 
Thomas Jefferson University Search Jefferson
Jefferson Medical College Jefferson College of Graduate Studies Jefferson College of Health Professions
Menu
Thomas Jefferson University - Diane E. Merry, PhD
Diane E. Merry, PhD

Biochemistry & Molecular Biology
Thomas Jefferson University
Jefferson Medical College
Department of Biochemistry & Molecular Biology
Associate Professor

Mailing Address
233 South 10th Street, 228 BLSB
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: (215) 503-4907
Fax: (215) 923-9162
Diane.Merry@jefferson.edu
Qualifications
Ph.D. (1991) University of Pennsylvania
Expertise and Research Interests
How does expansion of the polyglutamine tract in the androgen receptor cause motor neuron dysfunction and cell death?

The research in my lab centers on two areas of investigation to understand the molecular pathogenesis of the neurodegenerative disease spinal and bulbar muscular atrophy, which is caused by polyglutamine expansion within the androgen receptor (AR). 1) To understand the molecular basis for DHT-dependent AR misfolding, aggregation and toxicity; and 2) To develop an understanding of the molecular pathways by which motor neurons become dysfunctional in response to expression of the mutant protein. These studies are generally designed to understand how neurons respond to the accumulation of misfolded proteins.

SPINAL AND BULBAR MUSCULAR ATROPHY (SBMA): A MOTOR NEURON DISEASE CAUSED BY TRINUCLEOTIDE REPEAT EXPANSION. The expansion of a polyglutamine-encoding CAG trinucleotide repeat within the androgen receptor (AR) gene causes the motor neuron degenerative disease spinal and bulbar muscular atrophy. We have shown that androgen binding by the mutant polyglutamine-expanded AR is required for disease. Moreover, we have found that nuclear localization of the mutant AR is necessary, but not sufficient, to cause disease. Our focus now lies in understanding the steps downstream of hormone binding that impact toxicity.

The areas of investigation are based on the following questions.

AT WHAT POINT IN ANDROGEN RECEPTOR TRAFFICKING AND METABOLISM DO THINGS GO WRONG? The mutant AR, while normal in its transcriptional function, fails to be properly degraded. At what point in its life-cycle does its metabolism go awry? What roles do DNA binding, nuclear export and post-translational modifications play in AR aggregation and toxicity? What role does proteolytic cleavage play in disease? We have recently found that an interdomain interaction of the AR, the N/C interaction, plays a role in mutant AR aggregation and toxicity. Ongoing studies are evaluating the mechanism(s) underlying this finding.

WHY DO NUCLEAR NEURONAL PROTEASOMES FAIL TO EFFICIENTLY PROCESS EXPANDED POLYGLUTAMINE-CONTAINING PROTEINS? We have found that manipulation of the nuclear isoform of the 11S proteasomal regulator PA28 (PA28³) substantially modulates AR aggregation. Moreover, PA28³ protects motor neurons from mutant AR toxicity. Ongoing studies are evaluating the mechanism by which PA28³ is neuroprotective.

WHERE DO WE TURN FOR THERAPIES? Understanding the molecular details of mutant AR metabolism should lead us to novel therapeutic approaches. Based on our finding that the N/C interaction plays a role in AR aggregation and toxicity, we have identified several AR ligands that prevent the N/C interaction and promote motor neuron viability. Preclinical studies of these compounds in a transgenic mouse model of SBMA are ongoing.

Approaches: We utilize biochemical, molecular and cell biological approaches to address the questions under investigation. Our systems primarily include transgenic mice, cultured cell models, and primary motor neuron cultures.



Keywords
Biochemistry; Neurodegeneration; Protein misfolding
Publications
  • Merry, D. E., Kobayashi, Y., Bailey, C. K., Taye, A. A., and Fischbeck, K. H.: Cleavage, aggregation, and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum. Molec. Genet. 7:693-701, 1998.
  • Li, M., Miwa, S., Kobayashi, Y., Merry, D. E., Yamamoto, M., Tanaka, F., Doyu, M., Hashizume, Y., Fischbeck, K. H., and Sobue, G.: Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann. Neurol. 44:249-254, 1998.
  • Li. M., Nakagomi, Y., Kobayashi, Y., Merry, D. E., Tanaka, F., Doyu, M., Mitsuma, T., Fischbeck, K. H., and Sobue, G.: Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am. J. Path. 153:695-701, 1998.
  • Kobayashi, Y., Miwa, S., Merry, D. E., Kume, A., Mei, L., Doyu, M., and Sobue, G.: Caspase-3 cleaves the expanded androgen receptor protein of spinal and bulbar muscular atrophy in a polyglutamine repeat length-dependent manner. BBRC 252:145-150, 1998.
  • Nakamura, M., Raghupathi, R., Merry, D. E., Scherbel, U., Saatman, K. E., and McIntosh, T. K.: Overexpression of bcl-2 is neuroprotective after experimental brain injury in transgenic mice. J. Comp. Neurol. 412:681-692, 1999.
  • McCampbell, A., Taylor, J. P., Taye, A. A., Robitschek, J., Li, M., Walcott, J., Merry, D., Chai, Y., Paulson, H., Sobue, G., Fischbeck, K. H.: CBP sequestration by expanded polyglutamine-containing protein. Hum. Molec. Genet. 9:2197-2202, 2000.
  • Abel, A., Walcott, J., Woods, J., Duda, J., and Merry, D. E.: Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum. Molec. Genet. 10:107-116, 2001.
  • Bailey, C. K., Andriola, I. F. M., Kampinga, H. H., and Merry, D. E.: Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum. Molec. Genet., 11:515-523, 2002.
  • Luthi-Carter, R., Strand, A. D., Hanson, S. A., Kooperberg, C., Schilling, G., La Spada, A. R., Merry, D. E., Young, A. B., Ross, C. A., Borchelt, D. R., and Olson, J. M.: Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington's disease mouse models reveal context-independent effects. Hum. Molec. Genet. 11:1927-1937, 2002.
  • Chan, H. Y. E., Warrick, J. M., Andriola, I., Merry, D. E., and Bonini, N. M.: Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum. Molec. Genet. 11:2895-2904, 2002.
  • Walcott, J. L. and Merry, D. E.: Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy. J. Biol. Chem. 277:50855-50859, 2002.
  • Mandrusiak, L. M., Beitel, L. K., Wang, X. l., Scanlon, T. C., Merry, D. E., and Trifiro, M. A.: Transglutaminase potentiates ligand-dependent proteasome dysfunction induced by polyglutamine-expanded androgen receptor. Hum. Molec. Genet. 12:1497-1506, 2003.
  • Chevalier-Larsen, E.S., OBrien, C.J., Wang, H., Jenkins, S.C., Holder, L., Lieberman, A.P., and Merry, D.E.: Castration restores function to aged symptomatic males in a transgenic mouse model of SBMA. J. Neurosci. 24:4778-4786, 2004.
  • Li, M., Chevalier-Larsen, E.S., Merry, D.E., Diamond, M.I. : Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy. J Biol Chem. 282:3157-64, 2007.
  • Yang, Z., Chang, Y.J., Yu, I.C., Yeh, S., Wu, C.C., Miyamoto, H., Merry, D.E., Sobue, G., Chen, L.M., Chang, S.S., Chang, C. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nat Med.13:348-353, 2007.
  • Schiewer, M.J., Morey, L.M., Burd,, C.J., Liu, Y., Merry, D.E., Ho, S.-M. and Knudsen, K.E. Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer. Oncogene 28:1016-27, 2009.
  • Montie, H.L., Cho, M.S., Holder, L., Liu, Y., Tsvetkov, A., Finkbeiner, S. and Merry, D.E.: Cytoplasmic retention of polyQ-expanded androgen receptor ameliorates disease and induces autophagy in a mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet. 18:1937-50, 2009.
  • Mojsilovic-Petrovic, J., Nedelsky, N., Boccitto, M., Mano, I., Georgiades, S., Zhou, W., Liu, Y., Neve, R., Taylor, P., Driscoll, M., Clardy, J., Merry, D., and Kalb, R.: FOXO3a is broadly neuroprotective in vitro and in vivo against insults implicated in motor neuron diseases. J. Neurosci. J Neurosci. 29:8236-47, 2009.
  • Montie, H.L. and Merry, D.E.: Autophagy and access: Understanding the role of androgen receptor subcellular localization in SBMA. Autophagy 5:1194-1197, 2009.
  • Orr, C., Montie, H.L., Liu, Y., Bolzoni, E., Jenkins, S.C., Wilson, E.M., Joseph, J., McDonnell, D.P. and Merry, D.E.: An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy. J. Biol. Chem. Epub September 8, 2010.
  • Chevalier-Larsen, E.S. and Merry, D.E.: Testosterone treatment fails to accelerate disease in a transgenic mouse model of spinal and bulbar muscular atrophy. Dis Model Mech. 2011 Oct 4. [Epub ahead of print].

Individual Expertise profile of Diane E. Merry, PhD, Copyright © Diane E. Merry, PhD.
Last Updated by Admin : Tuesday, June 5, 2012 3:55:07 PM



 Printable Version

Thomas Jefferson University
Thomas Jefferson University