title: Mutant α-Synuclein Overexpression Induces Stressless Pacemaking in Vagal Motoneurons at Risk in Parkinson's Disease.
abstract: α-Synuclein overexpression (ASOX) drives the formation of toxic aggregates in neurons vulnerable in Parkinson's disease (PD), including dopaminergic neurons of the substantia nigra (SN) and cholinergic neurons of the dorsal motor nucleus of the vagus (DMV). Just as these populations differ in when they exhibit α-synucleinopathies during PD pathogenesis, they could also differ in their physiological responses to ASOX. An ASOX-mediated hyperactivity of SN dopamine neurons, which was caused by oxidative dysfunction of Kv4.3 potassium channels, was recently identified in transgenic (A53T-SNCA) mice overexpressing mutated human α-synuclein. Noting that DMV neurons display extensive α-synucleinopathies earlier than SN dopamine neurons while exhibiting milder cell loss in PD, we aimed to define the electrophysiological properties of DMV neurons in A53T-SNCA mice. We found that DMV neurons maintain normal firing rates in response to ASOX. Moreover, Kv4.3 channels in DMV neurons exhibit no oxidative dysfunction in the A53T-SNCA mice, which could only be recapitulated in wild-type mice by glutathione dialysis. Two-photon imaging of redox-sensitive GFP corroborated the finding that mitochondrial oxidative stress was diminished in DMV neurons in the A53T-SNCA mice. This reduction in oxidative stress resulted from a transcriptional downregulation of voltage-activated (Cav) calcium channels in DMV neurons, which led to a reduction in activity-dependent calcium influx via Cav channels. Thus, ASOX induces a homeostatic remodeling with improved redox signaling in DMV neurons, which could explain the differential vulnerability of SN dopamine and DMV neurons in PD and could promote neuroprotective strategies that emulate endogenous homeostatic responses to ASOX (e.g., stressless pacemaking) in DMV neurons.
  
  
  
  Overexpression of mutant α-synuclein causes Parkinson's disease, presumably by driving neurodegeneration in vulnerable neuronal target populations. However, the extent of α-synuclein pathology (e.g., Lewy bodies) is not directly related to the degree of neurodegeneration across various vulnerable neuronal populations. Here, we show that, in contrast to dopamine neurons in the substantia nigra, vagal motoneurons do not enhance their excitability and oxidative load in response to chronic mutant α-synuclein overexpression. Rather, by downregulating their voltage-activated calcium channels, vagal motoneurons acquire a stressless form of pacemaking that diminishes mitochondrial and cytosolic oxidative stress. Emulating this endogenous adaptive response to α-synuclein overexpression could lead to novel strategies to protect dopamine neurons and perhaps delay the onset of Parkinson's disease.
authors.affiliation: Department of Medical Neurobiology and.
authors.forename: Efrat
authors.identifier: 0000-0001-9868-7987
authors.initials: E
authors.lastname: Lasser-Katz
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences and the Institute of Life Sciences, The Hebrew University of Jerusalem, 9112102, Jerusalem, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Simchovitz
authors.affiliation: Department of Medical Neurobiology and.
authors.forename: Wei-Hua
authors.identifier: 0000-0001-5724-5680
authors.initials: WH
authors.lastname: Chiu
authors.affiliation: Department of Neurology, Philipps-University Marburg, 35043 Marburg, Germany, and.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Faculty of Medicine, and.
authors.forename: Ronit
authors.initials: R
authors.lastname: Sharon
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences and the Institute of Life Sciences, The Hebrew University of Jerusalem, 9112102, Jerusalem, Israel.
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
authors.affiliation: Institute of Neurophysiology, Neuroscience Center, Goethe-University, 60590 Frankfurt, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Roeper
authors.affiliation: Department of Medical Neurobiology and joshg@ekmd.huji.ac.il.
authors.forename: Joshua A
authors.identifier: 0000-0002-5740-4087
authors.initials: JA
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D001683:Biological Clocks; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D059290:Dopaminergic Neurons / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009046:Motor Neurons; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000503:physiopathology*; D051672:Shal Potassium Channels / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013378:Substantia Nigra / Q000166:cytology / Q000502:physiology; D014630:Vagus Nerve / Q000166:cytology / Q000502:physiology*; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D015220:Calcium Channels; C497604:SNCA protein, human; D051672:Shal Potassium Channels; D051844:alpha-Synuclein
keywords: Lewy pathology; acetylcholine; homeostasis; multiphoton microscopy; neurodegeneration; oxidative stress