This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yu, Z. Articles by Lieberman, A. P. Search for Related Content PubMed PubMed Citation Articles by Yu, Z. Articles by Lieberman, A. P.

(American Journal of Pathology. 2006;168:195-204.)
© 2006 American Society for Investigative Pathology

Abnormalities of Germ Cell Maturation and Sertoli Cell Cytoskeleton in Androgen Receptor 113 CAG Knock-In Mice Reveal Toxic Effects of the Mutant Protein

Zhigang Yu^*, Nahid Dadgar^*, Megan Albertelli, Arno Scheller, Roger L. Albin, Diane M. Robins and Andrew P. Lieberman^*

From the Departments of Pathology,^* Human Genetics, and Neurology, The University of Michigan Medical School; and the Geriatrics Research, Education, and Clinical Center, Ann Arbor VA Medical Center, Ann Arbor, Michigan

An unresolved question in the study of the polyglutamine neurodegenerative disorders is the extent to which partial loss of normal function of the mutant protein contributes to the disease phenotype. To address this, we studied Kennedy disease, a degenerative disorder of lower motor neurons caused by a CAG/glutamine expansion in the androgen receptor (Ar) gene. Signs of partial androgen insensitivity, including testicular atrophy and decreased fertility, are common in affected males, although the underlying mechanisms are not well understood. Here, we describe a knock-in mouse model that reproduces the testicular atrophy, diminished fertility, and systemic signs of partial androgen insensitivity that occur in Kennedy disease patients. Using this model, we demonstrate that the testicular pathology in this disorder is distinct from that mediated by loss of AR function. Testes pathology in 113 CAG knock-in mice was characterized by morphological abnormalities of germ cell maturation, decreased solubility of the mutant AR protein, and alterations of the Sertoli cell cytoskeleton, changes that are distinct from those produced by AR loss-of-function mutation in testicular feminization mutant mice. Our data demonstrate that toxic effects of the mutant protein mediate aspects of the Kennedy disease phenotype previously attributed to a loss of AR function.

This article has been cited by other articles:

				P. S. Thomas Jr, G. S. Fraley, V. Damien, L. B. Woodke, F. Zapata, B. L. Sopher, S. R. Plymate, and A. R. La Spada Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy Hum. Mol. Genet., July 15, 2006; 15(14): 2225 - 2238. [Abstract] [Full Text] [PDF]

				M. A. Albertelli, A. Scheller, M. Brogley, and D. M. Robins Replacing the Mouse Androgen Receptor with Human Alleles Demonstrates Glutamine Tract Length-Dependent Effects on Physiology and Tumorigenesis in Mice Mol. Endocrinol., June 1, 2006; 20(6): 1248 - 1260. [Abstract] [Full Text] [PDF]

				M. Thomas, J. M. Harrell, Y. Morishima, H.-M. Peng, W. B. Pratt, and A. P. Lieberman Pharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction Hum. Mol. Genet., June 1, 2006; 15(11): 1876 - 1883. [Abstract] [Full Text] [PDF]