Diane Merry, PhD

Contact Dr. Merry

900 Walnut St.

Philadelphia, PA 19107

(215) 503-4907
(215) 923-9162 fax

Research and Clinical Interests

Neurodegenerative diseases, Polyglutamine diseases, Androgen receptor structure and function

The research in my lab centers on understanding the molecular pathways by which motor neurons become dysfunctional in response to expression of polyglutamine-expanded androgen receptor in the neurodegenerative disease spinal and bulbar muscular atrophy. 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. 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 nuclear import, nuclear export, DNA binding, and post-translational modifications play in the regulation of AR catabolism? What role does proteolytic cleavage play in disease?

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 substantially modulates AR aggregation. Ongoing studies evaluate whether PA28gamma is required for disease and whether it is involved in the normal degradation of AR.

Where do we turn for therapies? Understanding the molecular details of mutant AR metabolism should lead us to novel therapeutic approaches. We have identified several compounds that promote the turnover of expanded AR; these are currently under evaluation for therapeutic development.

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.

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Publications

Most recent Peer-reviewed Publications

1. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation
2. A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability
3. Attacking the flank: Targeting new pathways in SBMA
4. Guidelines for the use and interpretation of assays for monitoring autophagy
5. Testosterone treatment fails to accelerate disease in a transgenic mouse model of spinal and bulbar muscular atrophy
6. SIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA
7. An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy
8. Autophagy and access: Understanding the role of androgen receptor subcellular localization in SBMA
9. FOXO3a is broadly neuroprotective in vitro and in vivo against insults implicated in motor neuron diseases
10. Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy
11. Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer
12. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor
13. Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy
14. Animal models of Kennedy disease
15. Castration restores function and neurofilament alterations of aged symptomatic males in a transgenic mouse model of spinal and bulbar muscular atrophy
16. Transglutaminase potentiates ligand-dependent proteasome dysfunction induced by polyglutamine-expanded androgen receptor
17. Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy
18. Trinucleotide repeat disease. The androgen receptor in spinal and bulbar muscular atrophy
19. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells
20. Polyglutamine and transcription: Gene expression changes shared by DRPLA and Huntington's disease mouse models reveals context-independent effects

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