 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
The Journal of Neuroscience, November 22, 2006, 26(47):12106-12117; doi:10.1523/JNEUROSCI.3032-06.2006
Previous Article | Next Article
Neurobiology of Disease
Reversible Disruption of Dynactin 1-Mediated Retrograde Axonal Transport in Polyglutamine-Induced Motor Neuron Degeneration
Masahisa Katsuno, Hiroaki Adachi, Makoto Minamiyama, Masahiro Waza, Keisuke Tokui, Haruhiko Banno, Keisuke Suzuki, Yu Onoda, Fumiaki Tanaka, Manabu Doyu, andGen Sobue Department of Neurology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan
Correspondence should be addressed to Dr. Gen Sobue, Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Email: sobueg{at}med.nagoya-u.ac.jp
Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease caused by an expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the androgen receptor (AR) gene. To elucidate the pathogenesis of polyglutamine-mediated motor neuron dysfunction, we investigated histopathological and biological alterations in a transgenic mouse model of SBMA carrying human pathogenic AR. In affected mice, neurofilaments and synaptophysin accumulated at the distal motor axon. A similar intramuscular accumulation of neurofilament was detected in the skeletal muscle of SBMA patients. Fluoro-gold labeling and sciatic nerve ligation demonstrated an impaired retrograde axonal transport in the transgenic mice. The mRNA level of dynactin 1, an axon motor for retrograde transport, was significantly reduced in the SBMA mice resulting from pathogenic AR-induced transcriptional dysregulation. These pathological events were observed before the onset of neurological symptoms, but were reversed by castration, which prevents nuclear accumulation of pathogenic AR. Overexpression of dynactin 1 mitigated neuronal toxicity of the pathogenic AR in a cell culture model of SBMA. These observations indicate that polyglutamine-dependent transcriptional dysregulation of dynactin 1 plays a crucial role in the reversible neuronal dysfunction in the early stage of SBMA.
Key words: polyglutamine; spinal and bulbar muscular atrophy; androgen; neurofilament; axonal transport; retrograde; dynactin
Received July 18, 2006; revised Sept. 21, 2006; accepted Oct. 6, 2006.
Correspondence should be addressed to Dr. Gen Sobue, Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Email: sobueg{at}med.nagoya-u.ac.jp
Related articles in J. Neurosci.:
- This Week in The Journal
J. Neurosci. 2006 26: i.[Full Text]
This article has been cited by other articles:
Y. Iguchi, M. Katsuno, J.-i. Niwa, S.-i. Yamada, J. Sone, M. Waza, H. Adachi, F. Tanaka, K.-i. Nagata, N. Arimura, et al.
TDP-43 Depletion Induces Neuronal Cell Damage through Dysregulation of Rho Family GTPases
J. Biol. Chem., August 14, 2009; 284(33): 22059 - 22066.
[Abstract] [Full Text] [PDF]
D. A. Monks, J. A. Johansen, K. Mo, P. Rao, B. Eagleson, Z. Yu, A. P. Lieberman, S. M. Breedlove, and C. L. Jordan
Overexpression of wild-type androgen receptor in muscle recapitulates polyglutamine disease
PNAS, November 13, 2007; 104(46): 18259 - 18264.
[Abstract] [Full Text] [PDF]
A. Kaasik, D. Safiulina, V. Choubey, M. Kuum, A. Zharkovsky, and V. Veksler
Mitochondrial Swelling Impairs the Transport of Organelles in Cerebellar Granule Neurons
J. Biol. Chem., November 9, 2007; 282(45): 32821 - 32826.
[Abstract] [Full Text] [PDF]
H. Adachi, M. Waza, K. Tokui, M. Katsuno, M. Minamiyama, F. Tanaka, M. Doyu, and G. Sobue
CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model
J. Neurosci., May 9, 2007; 27(19): 5115 - 5126.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|