title: Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons.
abstract: Although the mechanisms underlying the loss of neurons in Parkinson's disease are not well understood, impaired mitochondrial function and pathological protein aggregation are suspected as playing a major role. Why DA (dopamine) neurons and a select small subset of brain nuclei are particularly vulnerable to such ubiquitous cellular dysfunctions is presently one of the key unanswered questions in Parkinson's disease research. One intriguing hypothesis is that their heightened vulnerability is a consequence of their elevated bioenergetic requirements. Here, we show for the first time that vulnerable nigral DA neurons differ from less vulnerable DA neurons such as those of the VTA (ventral tegmental area) by having a higher basal rate of mitochondrial OXPHOS (oxidative phosphorylation), a smaller reserve capacity, a higher density of axonal mitochondria, an elevated level of basal oxidative stress, and a considerably more complex axonal arborization. Furthermore, we demonstrate that reducing axonal arborization by acting on axon guidance pathways with Semaphorin 7A reduces in parallel the basal rate of mitochondrial OXPHOS and the vulnerability of nigral DA neurons to the neurotoxic agents MPP(+) (1-methyl-4-phenylpyridinium) and rotenone. Blocking L-type calcium channels with isradipine was protective against MPP(+) but not rotenone. Our data provide the most direct demonstration to date in favor of the hypothesis that the heightened vulnerability of nigral DA neurons in Parkinson's disease is directly due to their particular bioenergetic and morphological characteristics.
authors: Departments of Pharmacology and Neurosciences, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Université de Montréal, Montréal, QC H4T 1J4, Canada.
authors: Consiglia
authors: C
authors: Pacelli
authors: Departments of Pharmacology and Neurosciences, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Université de Montréal, Montréal, QC H4T 1J4, Canada.
authors: Nicolas
authors: N
authors: Giguère
authors: Departments of Pharmacology and Neurosciences, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Université de Montréal, Montréal, QC H4T 1J4, Canada.
authors: Marie-Josée
authors: MJ
authors: Bourque
authors: Department of Psychiatry and Neurosciences, Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Faculté de Médecine, Université Laval, Québec, QC G1J 2G3, Canada.
authors: Martin
authors: M
authors: Lévesque
authors: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors: Ruth S
authors: RS
authors: Slack
authors: Departments of Pharmacology and Neurosciences, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Université de Montréal, Montréal, QC H4T 1J4, Canada. Electronic address: louis-eric.trudeau@umontreal.ca.
authors: Louis-Éric
authors: LÉ
authors: Trudeau
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000502:physiology*; D004734:Energy Metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009473:Neuronal Plasticity; D009498:Neurotoxins / Q000494:pharmacology; D010085:Oxidative Phosphorylation; D010300:Parkinson Disease / Q000378:metabolism; D065842:Pars Compacta / Q000502:physiology; D012402:Rotenone / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000502:physiology
chemical_list: D009498:Neurotoxins; D012402:Rotenone; D006861:Hydrogen Peroxide; D015655:1-Methyl-4-phenylpyridinium