title: Mutant α-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of A-type potassium channels.
abstract: Parkinson disease (PD) is an α-synucleinopathy resulting in the preferential loss of highly vulnerable dopamine (DA) substantia nigra (SN) neurons. Mutations (e.g., A53T) in the α-synuclein gene (SNCA) are sufficient to cause PD, but the mechanism of their selective action on vulnerable DA SN neurons is unknown. In a mouse model overexpressing mutant α-synuclein (A53T-SNCA), we identified a SN-selective increase of in vivo firing frequencies in DA midbrain neurons, which was not observed in DA neurons in the ventral tegmental area. The selective and age-dependent gain-of-function phenotype of A53T-SCNA overexpressing DA SN neurons was in part mediated by an increase of their intrinsic pacemaker frequency caused by a redox-dependent impairment of A-type Kv4.3 potassium channels. This selective enhancement of "stressful pacemaking" of DA SN neurons in vivo defines a functional response to mutant α-synuclein that might be useful as a novel biomarker for the "DA system at risk" before the onset of neurodegeneration in PD.
authors.affiliation: Institute of Neurophysiology, Neuroscience Center.
authors.forename: Mahalakshmi
authors.initials: M
authors.lastname: Subramaniam
authors.affiliation: Institute of Physiology II.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-6078-9811
authors.initials: D
authors.lastname: Althof
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, 60590 Frankfurt, Germany, and.
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.affiliation: Institute of Physiology II.
authors.forename: Jochen
authors.initials: J
authors.lastname: Schwenk
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, 60590 Frankfurt, Germany, and.
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.affiliation: Institute of Physiology II, BIOSS Centre for Biological Signaling Studies, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: Akos
authors.initials: A
authors.lastname: Kulik
authors.affiliation: Institute of Physiology II.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fakler
authors.affiliation: Institute of Neurophysiology, Neuroscience Center, roeper@em.uni-franfurt.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Roeper
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D059290:Dopaminergic Neurons / Q000502:physiology*; D055724:Electrophysiological Phenomena; D005978:Glutathione / Q000378:metabolism / Q000502:physiology; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D051672:Shal Potassium Channels / Q000502:physiology*; D013378:Substantia Nigra / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000254:growth & development / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D051672:Shal Potassium Channels; D051844:alpha-Synuclein; D005978:Glutathione
keywords: A-type K channel; dopamine; in vivo; redox; substantia nigra; α-synuclein