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Brain Advance Access published online on January 19, 2005
Brain, doi:10.1093/brain/awh381
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Brain © Guarantors of Brain 2005; all rights reserved
Received June 15, 2004
Revised November 26, 2004
Accepted November 30, 2004

Article

Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients

Hiroaki Adachi 1, Masahisa Katsuno 1, Makoto Minamiyama 1, Masahiro Waza 1, Chen Sang 1, Yuji Nakagomi 2, Yasushi Kobayashi 1, Fumiaki Tanaka 1, Manabu Doyu 1, Akira Inukai 1, Mari Yoshida 3, Yoshio Hashizume 3, and Gen Sobue 1*

1 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
2 Central Research Laboratories, School of Medicine, Aichi Medical University, Japan
3 Department of Neuropathology, Institute for Medical Sciences of Aging, Aichi Medical University of Aichi, Japan

* To whom correspondence should be addressed.
Gen Sobue, E-mail: sobueg{at}med.nagoya-u.ac.jp


  Abstract

Summary Spinal and bulbar muscular atrophy (SBMA) is an inherited adult onset motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR), affecting only males. The characteristic pathological finding is nuclear inclusions (NIs) consisting of mutant AR with an expanded polyQ in residual motor neurons, and in certain visceral organs. We immunohistochemically examined 11 SBMA patients at autopsy with 1C2, an antibody that specifically recognizes expanded polyQ. Our study demonstrated that diffuse nuclear accumulation of mutant AR was far more frequent and extensive than NIs being distributed in a wide array of CNS nuclei, and in more visceral organs than thus far believed. Mutant AR accumulation was also present in the cytoplasm, particularly in the Golgi apparatus; nuclear or cytoplasmic predominance of accumulation was tissue specific. Furthermore, the extent of diffuse nuclear accumulation of mutant AR in motor and sensory neurons of the spinal cord was closely related to CAG repeat length. Thus, diffuse nuclear accumulation of mutant AR apparently is a cardinal pathogenetic process underlying neurological manifestations, as in SBMA transgenic mice, while cytoplasmic accumulation may also contribute to SBMA pathophysiology.

Keywords: polyglutamine; spinal and bulbar muscular atrophy; diffuse nuclear accumulation; nuclear inclusion, cytoplasmic accumulation.
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