title: Calcium entry and α-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons.
abstract: The core motor symptoms of Parkinson's disease (PD) are attributable to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial oxidant stress is widely viewed a major factor in PD pathogenesis. Previous work has shown that activity-dependent calcium entry through L-type channels elevates perinuclear mitochondrial oxidant stress in SNc dopaminergic neurons, providing a potential basis for their selective vulnerability. What is less clear is whether this physiological stress is present in dendrites and if Lewy bodies, the major neuropathological lesion found in PD brains, exacerbate it. To pursue these questions, mesencephalic dopaminergic neurons derived from C57BL/6 transgenic mice were studied in primary cultures, allowing for visualization of soma and dendrites simultaneously. Many of the key features of in vivo adult dopaminergic neurons were recapitulated in vitro. Activity-dependent calcium entry through L-type channels increased mitochondrial oxidant stress in dendrites. This stress progressively increased with distance from the soma. Examination of SNc dopaminergic neurons ex vivo in brain slices verified this pattern. Moreover, the formation of intracellular α-synuclein Lewy-body-like aggregates increased mitochondrial oxidant stress in perinuclear and dendritic compartments. This stress appeared to be extramitochondrial in origin, because scavengers of cytosolic reactive oxygen species or inhibition of NADPH oxidase attenuated it. These results show that physiological and proteostatic stress can be additive in the soma and dendrites of vulnerable dopaminergic neurons, providing new insight into the factors underlying PD pathogenesis.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Dilyan I
authors.initials: DI
authors.lastname: Dryanovski
authors.forename: Jaime N
authors.initials: JN
authors.lastname: Guzman
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xie
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Galteri
authors.forename: Laura A
authors.initials: LA
authors.lastname: Volpicelli-Daley
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miller
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D064026:Calbindins; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003712:Dendrites / Q000378:metabolism* / Q000648:ultrastructure; D059290:Dopaminergic Neurons / Q000166:cytology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism* / Q000494:pharmacology; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: C485995:Cacna1d protein, mouse; D064026:Calbindins; D020746:Calcium Channels, L-Type; D016166:Free Radical Scavengers; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D064030:S100 Calcium Binding Protein G; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D020122:tert-Butylhydroperoxide; D014446:Tyrosine 3-Monooxygenase; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D000111:Acetylcysteine