A distinct death mechanism is induced by 1-methyl-4-phenylpyridinium or by 6-hydroxydopamine in cultured rat cortical neurons: degradation and dephosphorylation of tau.
We examined whether the well-known neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion (MPP(+)) recruit distinct cell death mechanisms using primary cultured neurons derived from day 16 embryonic rat cortices. Electron microscopy revealed that cell death induced by both 6-OHDA and MPP(+) was typified by a condensation of chromatin while prominent mitochondrial swelling was observed only in those cells treated with MPP(+). Co-treatment of cells with a pan-caspase inhibitor, Z-VAD-fmk, attenuated 6-OHDA-induced chromatin condensation and neuronal death. Co-treatment with such antioxidants as N-acetylcysteine or Mn-TBAP also suppressed 6-OHDA-induced cell death. None of these treatments attenuated MPP(+)-induced cell death although caspase inhibition abolished MPP(+)-induced chromatin condensation. Interestingly, in these paradigms of cell death, the N-terminus of tau was specifically cleaved and the levels of phosphorylated tau were markedly decreased following 6-OHDA treatment. By contrast, the C-terminus of tau was cleaved in MPP(+)-induced cell death while the levels of phosphorylated tau remained largely unaltered. Taken together, our results indicate that distinct cellular mechanisms appear to underlie neurotoxin-induced cortical neuronal cell death.
Han
Baek Soo
BS
Department of Biology, Yonsei University College of Science, 134 Shinchon-Dong, Seodaemoon-Gu, 120-749, Seoul, South Korea.
Noh
Jai Sung
JS
Gwag
Byoung Joo
BJ
Oh
Young J
YJ
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D018929:Cell Culture Techniques; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D016166:Free Radical Scavengers / Q000494:pharmacology; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016627:Oxidopamine / Q000633:toxicity*; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D016166:Free Radical Scavengers; D010446:Peptide Fragments; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D016875:tau Proteins; D016627:Oxidopamine; D013482:Superoxide Dismutase; D015655:1-Methyl-4-phenylpyridinium; D000111:Acetylcysteine