title: Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients.
abstract: 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.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.forename: Makoto
authors.initials: M
authors.lastname: Minamiyama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Waza
authors.forename: Chen
authors.initials: C
authors.lastname: Sang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakagomi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Manabu
authors.initials: M
authors.lastname: Doyu
authors.forename: Akira
authors.initials: A
authors.lastname: Inukai
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D015388:Organelles / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine