title: The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons.
abstract: 6-hydroxydopamine (6-OHDA) is one of the most commonly used toxins for modeling degeneration of dopaminergic (DA) neurons in Parkinson's disease. 6-OHDA also causes axonal degeneration, a process that appears to precede the death of DA neurons. To understand the processes involved in 6-OHDA-mediated axonal degeneration, a microdevice designed to isolate axons fluidically from cell bodies was used in conjunction with green fluorescent protein (GFP)-labeled DA neurons. Results showed that 6-OHDA quickly induced mitochondrial transport dysfunction in both DA and non-DA axons. This appeared to be a general effect on transport function since 6-OHDA also disrupted transport of synaptophysin-tagged vesicles. The effects of 6-OHDA on mitochondrial transport were blocked by the addition of the SOD1-mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), as well as the anti-oxidant N-acetyl-cysteine (NAC) suggesting that free radical species played a role in this process. Temporally, microtubule disruption and autophagy occurred after transport dysfunction yet before DA cell death following 6-OHDA treatment. The results from the study suggest that ROS-mediated transport dysfunction occurs early and plays a significant role in inducing axonal degeneration in response to 6-OHDA treatment.
authors.forename: Xi
authors.initials: X
authors.lastname: Lu
authors.forename: Jeong Sook
authors.initials: JS
authors.lastname: Kim-Han
authors.forename: Steve
authors.initials: S
authors.lastname: Harmon
authors.affiliation: Department of Biomedical Engineering, Washington University in Saint Louis, 1 Brookings Drive, Campus Box 1097, St, Louis, MO 63130, USA. sakiyama@wustl.edu.
authors.forename: Shelly E
authors.initials: SE
authors.lastname: Sakiyama-Elbert
authors.forename: Karen L
authors.initials: KL
authors.lastname: O'Malley
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity*; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology
chemical_list: D018663:Adrenergic Agents; D016627:Oxidopamine