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Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death‐associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson's disease: protection by α‐lipoic acid
Author(s) -
Karunakaran Smitha,
Diwakar Latha,
Saeed Uzma,
Agarwal Varsha,
Ramakrishnan Sujanitha,
Iyengar Soumya,
Ravindranath Vijayalakshmi
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7580com
Subject(s) - pars compacta , substantia nigra , mptp , death associated protein 6 , ask1 , dopaminergic , neurodegeneration , microbiology and biotechnology , biology , neuroprotection , kinase , chemistry , protein kinase a , neuroscience , biochemistry , dopamine , cyclin dependent kinase 2 , medicine , transcription factor , nuclear protein , disease , gene
Parkinson's disease (PD), a neurodegenerative disorder, causes severe motor impairment due to loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MPTP, a neurotoxin that causes dopaminergic cell loss in mice, was used in an animal model to study the pathogenic mechanisms leading to neurodegeneration. We observed the activation of apoptosis signal regulating kinase (ASK1, MAPKKK) and phosphorylation of its downstream targets MKK4 and JNK, 12 h after administration of a single dose of MPTP. Further, Daxx, the death‐associated protein, translocated to the cytosol selectively in SNpc neurons seemingly due to MPTP mediated down‐regulation of DJ‐1, the redox‐sensitive protein that binds Daxx in the nucleus. Coadministration of a‐lipoic acid (ALA), a thiol antioxidant, abolished the activation of ASK1 and phosphorylation of downstream kinases, MKK4, and JNK and prevented the down‐regulation of DJ‐1 and translocation of Daxx to the cytosol seen after MPTP. ALA also attenuated dopaminergic cell loss in SNpc seen after subchronic MPTP treatment. Our studies demonstrate for the first time that MPTP triggers death signaling pathway by activating ASK1 and translocating Daxx, in vivo, in dopaminergic neurons in SNpc of mice and thiol antioxidants, such as ALA terminate this cascade and afford neuroprotection.–Karunakaran S., Diwakar, L., Saeed, U., Agarwal, V., Ramakrishnan, S., Iyengar, S., Ravindranath V. Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death associated protein, Daxx in substantia nigra pars compacta in a mouse model of Parkinson's disease: Protection by α‐lipoic acid. FASEB J. 21, 2226–2236 (2007)