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

• Published in: Brain (London, England : 1878) England : 1878), 2005-03, Vol.128 (3), p.659-670
• Main Authors: Adachi, Hiroaki, Katsuno, Masahisa, Minamiyama, Makoto, Waza, Masahiro, Sang, Chen, Nakagomi, Yuji, Kobayashi, Yasushi, Tanaka, Fumiaki, Doyu, Manabu, Inukai, Akira, Yoshida, Mari, Hashizume, Yoshio, Sobue, Gen
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; AR = androgen receptor; Biological and medical sciences; CBP = CREB-binding protein; Cell Nucleus - metabolism; Cytoplasm - metabolism; cytoplasmic accumulation; diffuse nuclear accumulation; DRPLA = dentatorubral-pallidoluysian atrophy; Humans; Immunoenzyme Techniques; Injuries of the nervous system and the skull. Diseases due to physical agents; Intranuclear Inclusion Bodies - metabolism; Intranuclear Inclusion Bodies - ultrastructure; Male; Medical sciences; Middle Aged; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; Mutation; Neurology; NIs = nuclear inclusions; nuclear inclusion; Organelles - metabolism; Peptides - metabolism; polyglutamine; polyQ = polyglutamine; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; SBMA = spinal and bulbar muscular atrophy; spinal and bulbar muscular atrophy; Tissue Distribution; Traumas. Diseases due to physical agents
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awh381

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.