title: Death of cortical and striatal neurons induced by mitochondrial defect involves differential molecular mechanisms.
abstract: An important aspect of Huntington's disease (HD) pathogenesis which may have important therapeutic implications is that the cellular events leading to cell death may be different in cortical and striatal neurons. In the present study, we characterized cellular changes in cortical and striatal neurons treated with the mitochondrial toxin 3-nitropropionic acid (3NP) in culture. Degeneration induced by 3NP was similar in both striatal and cortical neurons as observed using markers of cell viability and DNA fragmentation. However, in striatal neurons, 3NP produced a marked delocalization of Bad, Bax, cytochrome c and Smac while this was not observed in cortical neurons. Death of striatal neurons was preceded by activation of calpain and was blocked by calpain inhibitor I. In cortical neurons, calpain was not activated and calpain inhibitor I was without effect. In both cell types, caspase-9 and -3 were not activated by 3NP and the caspase inhibitor zVAD-fmk did not provide neuroprotective effect. Interestingly, treatment with staurosporine (STS) triggered caspase-9 and -3 in cortical and striatal cells, suggesting that the molecular machinery related to caspase-dependent apoptosis was functional in both cell types even though this machinery was not involved in 3NP toxicity. The present results clearly demonstrate that under mitochondrial inhibition, striatal and cortical neurons die through different pathways. This suggests that mitochondrial defects in HD may trigger the death of cortical and striatal neurons through different molecular events.
authors.affiliation: Laboratoire de Neurophysiologie, ULB-Erasme, 1070 Brussels, Belgium.
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Galas
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bizat
authors.forename: Laetitia
authors.initials: L
authors.lastname: Cuvelier
authors.forename: Kadiombo
authors.initials: K
authors.lastname: Bantubungi
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: Serge N
authors.initials: SN
authors.lastname: Schiffmann
authors.forename: David
authors.initials: D
authors.lastname: Blum
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D006816:Huntington Disease / Q000201:enzymology* / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity; D009574:Nitro Compounds; D011422:Propionates / Q000633:toxicity; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; C494821:Bad protein, rat; C494828:Bax protein, rat; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C489013:DIABLO protein, rat; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D045304:Cytochromes c; D020169:Caspases; C015392:3-nitropropionic acid