Omi / HtrA2 is relevant to the selective vulnerability of striatal neurons in Huntington's disease.
Selective vulnerability of neurons is a critical feature of neurodegenerative diseases, but the underlying molecular mechanisms remain largely unknown. We here report that Omi/HtrA2, a mitochondrial protein regulating survival and apoptosis of cells, decreases selectively in striatal neurons that are most vulnerable to the Huntington's disease (HD) pathology. In microarray analysis, Omi/HtrA2 was decreased under the expression of mutant huntingtin (htt) in striatal neurons but not in cortical or cerebellar neurons. Mutant ataxin-1 (Atx-1) did not affect Omi/HtrA2 in any type of neuron. Western blot analysis of primary neurons expressing mutant htt also confirmed the selective reduction of the Omi/HtrA2 protein. Immunohistochemistry with a mutant htt-transgenic mouse line and human HD brains confirmed reduction of Omi/HtrA2 in striatal neurons. Overexpression of Omi/HtrA2 by adenovirus vector reverted mutant htt-induced cell death in primary neurons. These results collectively suggest that the homeostatic but not proapoptotic function of Omi/HtrA2 is linked to selective vulnerability of striatal neurons in HD pathology.
Inagaki
Reina
R
Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Tagawa
Kazuhiko
K
Qi
Mei-Ling
ML
Enokido
Yasushi
Y
Ito
Hikaru
H
Tamura
Takuya
T
Shimizu
Shigeomi
S
Oyanagi
Kityomitsu
K
Arai
Nobutaka
N
Kanazawa
Ichiro
I
Wanker
Erich E
EE
Okazawa
Hitoshi
H
D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006706:Homeostasis; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse