Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients.
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.
Adachi
Hiroaki
H
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Katsuno
Masahisa
M
Minamiyama
Makoto
M
Waza
Masahiro
M
Sang
Chen
C
Nakagomi
Yuji
Y
Kobayashi
Yasushi
Y
Tanaka
Fumiaki
F
Doyu
Manabu
M
Inukai
Akira
A
Yoshida
Mari
M
Hashizume
Yoshio
Y
Sobue
Gen
G
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
D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine