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Inhibition of apoptosis signal-regulating kinase 1 reduces endoplasmic reticulum stress and nuclear huntingtin fragments in a mouse model of Huntington disease.

Authors
 K. J. CHO  ;  B. I. LEE  ;  S. Y. CHEON  ;  H. W. KIM  ;  H. J. KIM  ;  G. W. KIM 
Citation
 NEUROSCIENCE, Vol.163(4) : 1128-1134, 2009 
Journal Title
 NEUROSCIENCE 
ISSN
 0306-4522 
Issue Date
2009
MeSH
Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Cell Nucleus/metabolism* ; Cerebral Cortex/physiopathology ; Corpus Striatum/pathology ; Corpus Striatum/physiopathology ; Cytosol/metabolism ; Disease Models, Animal ; Endoplasmic Reticulum/physiology* ; Huntingtin Protein ; Huntington Disease/pathology ; Huntington Disease/physiopathology* ; MAP Kinase Kinase Kinase 5/antagonists & inhibitors ; MAP Kinase Kinase Kinase 5/metabolism* ; Male ; Mice ; Mice, Transgenic ; Motor Activity/physiology ; Nerve Tissue Proteins/metabolism* ; Neurons/physiology ; Nuclear Proteins/metabolism* ; Stress, Physiological/physiology*
Keywords
apoptosis signal-regulating kinase 1 ; ER stress ; Huntington's disease ; neutralizing Ask1 ; brain-derived neurotrophic factor ; huntingtin fragments
Abstract
Huntington's disease (HD) is characterized clinically by chorea, psychiatric disturbances, and dementia, while it is characterized pathologically by neuronal inclusions as well as striatal and cortical neurodegeneration. The neurodegeneration arises from the loss of long projection neurons in the cortex and striatum. In this study, we investigated the role of apoptosis signal-regulating kinase 1 (Ask1) in the pathogenesis of HD. We analyzed the expression of Ask1 and huntingtin (htt) within the striatum and cortex and also examined the interaction of Ask1 with htt fragments in HD (R6/2) mice. Additionally, we inhibited Ask1 and analyzed the resulting changes in brain-derived neurotrophic factor (BDNF) expression, motor function, and striatal atrophy. Ask1 activity was blocked using an Ask1 antibody raised against the C-terminus of the Ask1 protein. The anti-Ask1 antibody was infused into the striatum of the HD mice for four weeks using a micro-osmotic pump. The levels of Ask1 protein and endoplasmic reticulum (ER) stress were increased in HD mice. Binding of inactivated Ask1 to htt fragments was more prevalent in the cytosol than the nucleus of cortical neurons. Binding of inactivated Ask1 to htt fragments prevented translocation of the htt fragments into the nucleus, resulting in an improvement in motor dysfunction and atrophy. In the normal state, active Ask1 may help htt fragments enter the nucleus, while inactivated Ask1 hinders this translocation by binding to but not releasing fragmented htt into the nucleus. We propose that Ask1 may interact with htt fragments and subsequently induce ER stress. BDNF depletion may be prevented by targeting Ask1; this would decrease ER stress and possibly ameliorate behavioral or anatomical abnormalities that accompany HD. Therefore, regulating the amounts and activity of the Ask1 protein is a novel strategy for treatment of HD.
Full Text
http://www.sciencedirect.com/science/article/pii/S0306452209012251
DOI
10.1016/j.neuroscience.2009.07.048
Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Gyung Whan(김경환) ORCID logo https://orcid.org/0000-0001-7053-4372
Kim, Hyun Woo(김현우)
Kim, Hyun Jeong(김현정)
Lee, Byung In(이병인)
Cheon, So Yeong(전소영)
Cho, Kyuong Joo(조경주)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/104942
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